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Liu X, Lv M, Feng B, Gong Y, Min Q, Wang Y, Wu Q, Chen J, Zhao D, Li J, Zhang W, Zhan Q. SQLE amplification accelerates esophageal squamous cell carcinoma tumorigenesis and metastasis through oncometabolite 2,3-oxidosqualene repressing Hippo pathway. Cancer Lett 2025; 621:217528. [PMID: 39924077 DOI: 10.1016/j.canlet.2025.217528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/17/2025] [Accepted: 02/02/2025] [Indexed: 02/11/2025]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide, characterized by a dismal prognosis and elusive therapeutic targets. Dysregulated cholesterol metabolism is a critical hallmark of cancer cells, facilitating tumor progression. Here, we used whole genome sequencing data from several ESCC cohorts to identify the important role of squalene epoxidase (SQLE) in promoting ESCC tumorigenesis and metastasis. Specifically, our findings highlight the significance of 2,3-oxidosqualene, an intermediate metabolite of cholesterol biosynthesis, synthesized by SQLE and metabolized by lanosterol synthase (LSS), as a key regulator of ESCC progression. Mechanistically, the interaction between 2,3-oxidosqualene and vinculin enhances the nuclear accumulation of Yes-associated protein 1 (YAP), thereby increasing YAP/TEAD-dependent gene expression and accelerating both tumor growth and metastasis. In a 4-nitroquinoline 1-oxide (4-NQO)-induced ESCC mouse model, overexpression of Sqle resulted in accelerated tumorigenesis compared to wild-type controls, highlighting the pivotal role of SQLE in vivo. Furthermore, elevated SQLE expression in ESCC patients correlates with a poorer prognoses, suggesting potential therapeutic avenues for treatment. In conclusion, our study elucidates the oncogenic function of 2,3-oxidosqualene as a naturally occurring metabolite and proposes modulation of its levels as a promising therapeutic strategy for ESCC.
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Affiliation(s)
- Xuesong Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Peking University International Cancer Institute, Beijing, 100191, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Mengzhu Lv
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Bicong Feng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Ying Gong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Qingjie Min
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Yan Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Qingnan Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Jie Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Dongyu Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Jinting Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Weimin Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China.
| | - Qimin Zhan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Peking University International Cancer Institute, Beijing, 100191, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China; Soochow University Cancer Institute, Suzhou, 215127, China; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China.
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2
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Sun L, Xu Z, Shuai M, Li C, Yang G, Xu S. Natural resistance to cancers in long-lived mammals: genomic mechanisms and experimental evidence to explain Peto's paradox. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1801-1814. [PMID: 40131646 DOI: 10.1007/s11427-024-2838-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 01/10/2025] [Indexed: 03/27/2025]
Abstract
Long-lived mammals are reported to have rare or considerably fewer instances of spontaneous tumors, suggesting they might have evolved specific or convergent mechanisms of cancer resistance to extend lifespan; however, the underlying mechanisms remain insufficiently explored. Here, we conducted comparative analysis across 60 mammalian genomes to investigate the genomic features associated with natural cancer resistance. We identified 296 strongly selected genes unique to long-lived species and associated with immune response, DNA repair, and cancer, which might contribute to cancer resistance and lifespan extension in long-lived species. Further, 229 convergent cancer-related genes were detected in the four extremely long-lived species and in-vitro assays confirmed a convergent mutation of LZTS1, shared by bowhead whales and naked mole rats, could suppress cancer development. Importantly, 16 genes were significantly related to both body weight and cancer, defined as candidate genes of Peto's paradox. Of them, the YAP1 gene, harboring the A214S mutation, was identified as a key gene that upregulated tumor suppression genes by localizing to the cytoplasm, which might prohibit cancer development in the large and long-lived cetaceans. These findings provide novel insights into the molecular mechanisms underlying natural cancer resistance in long-lived mammals and the biological basis of Peto's paradox.
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Affiliation(s)
- Linxia Sun
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China
| | - Zhikang Xu
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China
| | - Mengqi Shuai
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China
| | - Chengxu Li
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China
| | - Guang Yang
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China
| | - Shixia Xu
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China.
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3
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Liu Y, Ding J, Li S, Jiang A, Chen Z, Quan M. LPA released from dying cancer cells after chemotherapy inactivates Hippo signaling and promotes pancreatic cancer cell repopulation. Cell Oncol (Dordr) 2025; 48:655-671. [PMID: 39903418 DOI: 10.1007/s13402-025-01038-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2025] [Indexed: 02/06/2025] Open
Abstract
PURPOSE The Hippo pathway in the tumorigenesis and progression of PDAC, with lysophosphatidic acid (LPA) regulating the Hippo pathway to facilitate cancer progression. However, the impact of the Hippo signaling pathway on tumor repopulation in PDAC remains unreported. METHODS Direct and indirect co-culture models to investigate gemcitabine-induced apoptotic cells can facilitate the repopulation of residual tumor cells. Mass spectrometry analysis was conducted to assess the impact of gemcitabine treatment on the lipid metabolism of pancreatic cancer cells. ELISA assays confirmed gemcitabine promotes the release of LPA from apoptotic pancreatic cancer cells. The expression of Yes-associated protein 1 (YAP1) elucidated the underlying mechanism by which dying cells induce tumor repopulation using qRT-PCR and Western blot. We studied the biological function of pancreatic cancer cells using CCK-8, colony formation, and transwell invasion assays in vitro. Co-culture models were used to validate the impact of Hippo pathway on tumor repopulation, while flow cytometry was employed to assess the sensitivity of pancreatic cancer cells to gemcitabine in the context of Hippo pathway. RESULTS Gemcitabine-induced dying cells released LPA in a dose-dependent manner, which promoted the proliferation, clonal formation, and invasion of pancreatic cancer cells. Mechanistic studies showed that gemcitabine and LPA facilitated the translocation of YAP1 and induced the inactivation of the Hippo pathway. YAP1 overexpression significantly enhanced the activity of autotaxin, leading to stimulated pancreatic cancer cells to secrete LPA. This mechanism orchestrated a self-sustaining LPA-Hippo feedback loop, which drove the repopulation of residual tumor cells. Simultaneously, it was observed that suppressing LPA and YAP1 expression enhanced the sensitivity of pancreatic cancer cells to gemcitabine. CONCLUSION Our investigation indicated that targeting the LPA-YAP1 signaling pathway could serve as a promising strategy to augment the overall therapeutic efficacy against PDAC.
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Affiliation(s)
- Yuzhi Liu
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
| | - Jie Ding
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
| | - Shumin Li
- Department of Oncology and State Key Laboratory of Systems Medicine for Cancer of Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Anyi Jiang
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
| | - Zhiqin Chen
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
| | - Ming Quan
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
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Haripriya E, Hemalatha K, Matada GSP, Pal R, Das PK, Ashadul Sk MD, Mounika S, Viji MP, Aayishamma I, Jayashree KR. Advancements of anticancer agents by targeting the Hippo signalling pathway: biological activity, selectivity, docking analysis, and structure-activity relationship. Mol Divers 2025; 29:2829-2862. [PMID: 39436581 DOI: 10.1007/s11030-024-11009-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/30/2024] [Indexed: 10/23/2024]
Abstract
The Hippo signalling pathway is prominent and governs cell proliferation and stem cell activity, acting as a growth regulator and tumour suppressor. Defects in Hippo signalling and hyperactivation of its downstream effector's Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play roles in cancer development, implying that pharmacological inhibition of YAP and TAZ activity could be an effective cancer treatment strategy. Conversely, YAP and TAZ can also have beneficial effects in promoting tissue repair and regeneration following damage, therefore their activation may be therapeutically effective in certain instances. Recently, a complex network of intracellular and extracellular signalling mechanisms that affect YAP and TAZ activity has been uncovered. The YAP/TAZ-TEAD interaction leads to tumour development and the protein structure of YAP/TAZ-TEAD includes three interfaces and one hydrophobic pocket. There are clinical and preclinical trial drugs available to inhibit the hippo signalling pathway, but these drugs have moderate to severe side effects, so researchers are in search of novel, potent, and selective hippo signalling pathway inhibitors. In this review, we have discussed the hippo pathway in detail, including its structure, activation, and role in cancer. We have also provided the various inhibitors under clinical and preclinical trials, and advancement of small molecules their detailed docking analysis, structure-activity relationship, and biological activity. We anticipate that the current study will be a helpful resource for researchers.
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Affiliation(s)
- E Haripriya
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - K Hemalatha
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India.
| | - Gurubasavaraja Swamy Purawarga Matada
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - Rohit Pal
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India.
| | - Pronoy Kanti Das
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - M D Ashadul Sk
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - S Mounika
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - M P Viji
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - I Aayishamma
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - K R Jayashree
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
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Yang D, Sun W, Gao L, Zhao K, Zhuang Q, Cai Y. Cell competition as an emerging mechanism and therapeutic target in cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167769. [PMID: 40054587 DOI: 10.1016/j.bbadis.2025.167769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/18/2025] [Accepted: 02/27/2025] [Indexed: 03/17/2025]
Abstract
Cell competition, as an internal quality control mechanism that constantly monitor cell fitness and eliminate unfit cells, maintains proper embryogenesis and tissue integrity during early development and adult homeostasis. Recent studies have revealed that cell competition functions as a tumor-suppressive mechanism to defend against cancer by removing neoplastic cell, which however, is hijacked by tumor cells and drive cell competition in favor of mutant cells, thereby promoting cancer initiation and progression. In this review, with a special focus on mammalian systems, we discuss the latest insights into the mechanisms regulating cell competition and its dual role in tumor development. We also provide current strategies to modulate the direction of cell competition for the prevention and treatment of cancers.
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Affiliation(s)
- Dakai Yang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China.
| | - Wenyue Sun
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Lu Gao
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Kai Zhao
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China
| | - Qin Zhuang
- Department of General Practice, Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
| | - Yun Cai
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China.
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6
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Luo S, Huang Z, Dai Y, Wang S, Yu W, Li Z, Pu Q, Yang L, Yang T, Tang Y, Wang Z, Wang J, Wang J. Xihuang pill suppressed primary liver cancer growth by downregulation of AFP and YAP signaling. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119891. [PMID: 40294663 DOI: 10.1016/j.jep.2025.119891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 04/13/2025] [Accepted: 04/26/2025] [Indexed: 04/30/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xihuang Pill (XHP) is a traditional Chinese medicine formula that was originally used to treat malignant ulcers. Recent studies revealed its therapeutic effects on various malignant tumors. However, its potential efficacy and mechanisms in primary liver cancer (PLC) were not thoroughly investigated. AIM OF THE STUDY This study aimed to elucidate the efficacy and potential mechanisms of XHP in the treatment of PLC. METHODS An orthotopic PLC mice model was established adopting hydrodynamic tail vein injection method. Human liver cancer cell lines and organoids were utilized to assess the effect of XHP in vitro. The expressions of alpha-fetoprotein (AFP) and Yes-associated protein (YAP) were evaluated with western blotting. The mRNA expressions of YAP downstream targets were detected with qRT-PCR. Data from Liver Hepatocellular Carcinoma Collection of the Cancer Genome Atlas (TCGA-LIHC) were extracted to identify the potential targets of HCC. The major active components of XHP methanol extract and XHP medicated serum were detected by UHPLC-MS/MS. Human liver cancer cell lines were used to assess the efficacy and potential mechanisms of these active components in XHP in vitro. Finally, molecular docking was conducted to predict the binding affinities of XHP's active components with AFP and YAP. RESULTS XHP inhibited PLC tumor growth in the mice model with decreased AFP and Ki-67 index. In vitro, XHP suppressed the proliferation and migration of liver cancer cell lines in a time- and dose-dependent manner. Furthermore, even with a low concentration (5 mg/mL), XHP paralyzed the growth of PLC organoids derived from patients. Mechanistically, XHP downregulated the expression of AFP and YAP signaling in vitro and in vivo. UHPLC-MS/MS analysis identified 25 active components in XHP medicated serum. Among them, certain active compounds suppressed PLC cell proliferation and downregulated AFP and YAP signaling, suggesting their therapeutic potentials in PLC. Molecular docking indicated that several components in XHP exhibited strong binding affinities with both AFP and YAP. CONCLUSION XHP inhibited PLC growth by suppressing AFP and YAP signaling. This study provides an experimental basis for XHP application in PLC treatment.
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MESH Headings
- Animals
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- YAP-Signaling Proteins
- Signal Transduction/drug effects
- Down-Regulation/drug effects
- Mice
- alpha-Fetoproteins/metabolism
- alpha-Fetoproteins/genetics
- Cell Proliferation/drug effects
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Cell Line, Tumor
- Transcription Factors/metabolism
- Adaptor Proteins, Signal Transducing/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Male
- Mice, Nude
- Xenograft Model Antitumor Assays
- Mice, Inbred BALB C
- Molecular Docking Simulation
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Affiliation(s)
- Sha Luo
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yuewen Dai
- Beijing Fengtai Hospital of Integrated Traditional Chinese and Western Medicine, Beijing, China.
| | - Shuyang Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
| | - Wantao Yu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
| | - Zhihan Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
| | - Qing Pu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
| | - Lihui Yang
- Oncology Department, The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an, China.
| | - Tianyi Yang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
| | - Yu Tang
- Center of Pharmaceutical Technology, Tsinghua University, Beijing, China.
| | - Zhang Wang
- College of Ethnomedicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Jiabo Wang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing, China.
| | - Jingxiao Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China; Capital Medical University Research and Translational Laboratory for Traditional Chinese Medicine in the Prevention and Treatment of Infectious Severe Hepatitis, Beijing, China.
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Wei X, Zou L, Huang Y, Qiu C, Cheng G, Chen Y, Rao J. LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation. Biol Direct 2025; 20:64. [PMID: 40414964 DOI: 10.1186/s13062-025-00655-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 05/15/2025] [Indexed: 05/27/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the deadliest cancers globally. Yes-Associated Protein (YAP), a Hippo pathway effector, crucially regulates cell proliferation and apoptosis. Recent research has implicated YAP's role in HCC progression, but the mechanisms are unclear. This study aims to clarify YAP's function in HCC, emphasizing its regulation of key pathways and targets. RESULTS Gene knockout and overexpression models were established in nude mice and cell lines of HCC cells to investigate YAP's impact on tumorigenesis. Additionally, functional assays and molecular biology techniques were employed to identify YAP's regulatory networks. The study demonstrates that LDHA-regulated lactate production promotes YAP activation and malignant phenotypes in HCC. Overexpression of LDHA in HepG2 and Huh7 cells increased lactate levels and activated the YAP pathway, enhancing cell proliferation, migration, and invasion. Lactate treatment also promoted these malignant phenotypes by inhibiting YAP phosphorylation at Ser127. In a xenograft model, lactate accelerated tumor growth through YAP activation. YAP lactylation at K102 antagonized its Ser127 phosphorylation, further promoting malignant progression. CONCLUSIONS This study highlights the significance of YAP in HCC pathogenesis, providing insights into potential therapeutic targets for HCC management.
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Affiliation(s)
- Xiaoyong Wei
- Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China
| | - Long Zou
- Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China
| | - Yanqing Huang
- The Medical College of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Chuan Qiu
- The Medical College of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Guang Cheng
- Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China
| | - Ye Chen
- Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China
| | - Jun Rao
- Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi, 330029, China.
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8
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Wang L, Jin Y, Zhi Y, Li Z, Wang M, Wang B, Wang X. Effects of melatonin in polycystic ovary syndrome: is there Hippo pathway crosstalk? J Ovarian Res 2025; 18:101. [PMID: 40369589 PMCID: PMC12076993 DOI: 10.1186/s13048-025-01642-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 03/06/2025] [Indexed: 05/16/2025] Open
Abstract
OBJECTIVE Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder among reproductive women, characterized by hyperandrogenism, oligo-ovulation and polycystic ovarian morphology. Incorporating complementary medicine alongside traditional lifestyle therapies for PCOS may offer additional benefits for affected women. Melatonin (MT), a hormone secreted by the pineal gland, has emerged as a potential treatment for regulating ovarian function in PCOS. However, the specific effects and underlying mechanisms of MT on PCOS need to be elucidated. METHODS This review consolidates evidence from randomized controlled trials, original research articles, systematic reviews, and meta-analyses regarding MT supplementation in PCOS, with a particular focus on its interaction with the Hippo pathway, to provide a comprehensive overview of current knowledge. RESULTS Current evidence suggests that MT plays a role in modulating PCOS through various mechanisms and is associated with the Hippo pathway. However, several uncertainties and key limitations in the existing literature must be addressed before these treatments can be integrated into standard clinical practice. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Lijun Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Yuanyuan Jin
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Yuanyuan Zhi
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Zhenzhen Li
- Department of Pathology, Shandong Provincial Maternal and Child Health Care Hospital, Qingdao University, Jinan, 250014, China
| | - Meili Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Boda Wang
- Emergency Department, Xinji Town Central Health Center, Guanxian County, Liaocheng, 252500, China
| | - Xinbo Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China.
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China.
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Sun Y, Wei H, Yu W, Gao H, Li J, Li X, Zhang H, Zhang H, Miao S, Zhao L, Yang R, Xu J, Lu Y, Wei F, Zhou H, Gao D, Jin Y, Zhang L. The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis. Hepatology 2025; 81:1433-1451. [PMID: 39325963 DOI: 10.1097/hep.0000000000001063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 07/17/2024] [Indexed: 09/28/2024]
Abstract
BACKGROUND AND AIMS The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy. APPROACH AND RESULTS Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3K mut ) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC. CONCLUSIONS Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.
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Affiliation(s)
- Yang Sun
- Sheng Yushou Center of Cell Biology and Immunology, Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minghang, Shanghai, China
| | - Henan Wei
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Wentao Yu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Haoran Gao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Jinhui Li
- HuidaGene Therapeutics Co., Ltd., Shanghai, China
| | - Xiaoyu Li
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Haijiao Zhang
- Sheng Yushou Center of Cell Biology and Immunology, Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minghang, Shanghai, China
| | - Haoen Zhang
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Sen Miao
- Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Lihua Zhao
- Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Ruizeng Yang
- Sheng Yushou Center of Cell Biology and Immunology, Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minghang, Shanghai, China
| | - Jinjin Xu
- Sheng Yushou Center of Cell Biology and Immunology, Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minghang, Shanghai, China
| | - Yi Lu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Fang Wei
- Sheng Yushou Center of Cell Biology and Immunology, Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minghang, Shanghai, China
| | - Hu Zhou
- State Key Laboratory of Drug Research, Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Daming Gao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yunyun Jin
- Sheng Yushou Center of Cell Biology and Immunology, Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minghang, Shanghai, China
- Department of Emergency and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Lei Zhang
- Sheng Yushou Center of Cell Biology and Immunology, Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minghang, Shanghai, China
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
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10
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Liu Y, Zhu J, Jin Y, Sun Z, Wu X, Zhou H, Yang Y. Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation. Nat Commun 2025; 16:3583. [PMID: 40234449 PMCID: PMC12000370 DOI: 10.1038/s41467-025-58809-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 04/03/2025] [Indexed: 04/17/2025] Open
Abstract
Disruption of bile acid (BA) metabolism causes various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remains elusive. Here, we report that BA metabolism is directly controlled by a repressor function of YAP, which induces cholestasis by altering BA levels and composition via inhibiting the transcription activity of Fxr, a key physiological BA sensor. Elevated BA levels further activate hepatic YAP, resulting in a feedforward cycle leading to HCC. Mechanistically, Teads are found to bind Fxr in a DNA-binding-independent manner and recruit YAP to epigenetically suppress Fxr. Promoting BA excretion, or alleviating YAP repressor function by pharmacologically activating Fxr and inhibiting HDAC1, or overexpressing an Fxr target gene Bsep to promote BA exportation, alleviate cholestasis and HCC caused by YAP activation. Our results identify YAP's transcriptional repressor role in BA metabolism as a key driver of HCC and suggest its potential as a therapeutic target.
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MESH Headings
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Humans
- Bile Acids and Salts/metabolism
- YAP-Signaling Proteins
- Animals
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, Cytoplasmic and Nuclear/genetics
- Transcription Factors/metabolism
- Transcription Factors/genetics
- Mice
- Adaptor Proteins, Signal Transducing/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Male
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- Cell Line, Tumor
- Cell Cycle Proteins/metabolism
- Cholestasis/metabolism
- Cholestasis/genetics
- Gene Expression Regulation, Neoplastic
- Liver/metabolism
- Liver/pathology
- Hep G2 Cells
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Affiliation(s)
- Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Juanjuan Zhu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Yu Jin
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Zhonghe Sun
- Cancer Research Technology Program, Frederick National Laboratory for Cancer, Frederick, MD, USA
| | - Xiaolin Wu
- Cancer Research Technology Program, Frederick National Laboratory for Cancer, Frederick, MD, USA
| | - Huiping Zhou
- Department of Microbiology & Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
- Program in Gastrointestinal Malignancies, Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
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11
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Lv X, Liu J, Islam K, Ruan J, He C, Chen P, Huang C, Wang H, Dhar A, Moness M, Shi D, Murphy S, Zhao X, Yang S, Montoute I, Polakkattil A, Chung A, Ruiz E, Carbajal B, Padavala A, Chen L, Hua G, Chen X, Davis JS, Wang C. Hyperactivated YAP1 is essential for sustainable progression of renal clear cell carcinoma. Oncogene 2025:10.1038/s41388-025-03354-8. [PMID: 40210757 DOI: 10.1038/s41388-025-03354-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 02/12/2025] [Accepted: 03/17/2025] [Indexed: 04/12/2025]
Abstract
The most notable progress in renal clear cell carcinoma (ccRCC) in the past decades is the introduction of drugs targeting the VHL-HIF signaling pathway-associated angiogenesis. However, mechanisms underlying the development of VHL mutation-independent ccRCC are unclear. Here we provide evidence that the disrupted Hippo-YAP signaling contributes to the development of ccRCC independent of VHL alteration. We found that YAP1 and its primary target genes are frequently upregulated in ccRCC and the upregulation of these genes is associated with unfavorable patient outcomes. Research results derived from our in vitro and in vivo experimental models demonstrated that, under normoxic conditions, hyperactivated YAP1 drives the expression of FGFs to stimulate the proliferation of tumor and tumor-associated endothelial cells in an autocrine/paracrine manner. When rapidly growing cancer cells create a hypoxic environment, hyperactivated YAP1 in cancer cells induces the production of VEGF, which promotes the angiogenesis of tumor-associated endothelial cells, leading to improved tumor microenvironment and continuous tumor growth. Our study indicates that hyperactivated YAP1 is essential for maintaining ccRCC progression, and targeting the dual role of hyperactivated YAP1 represents a novel strategy to improve renal carcinoma therapy.
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Affiliation(s)
- Xiangmin Lv
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jiyuan Liu
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Kazi Islam
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jinpeng Ruan
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Chunbo He
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Obstetrics and Gynecology, Olson Center for Women's Health, University of Nebraska Medical Center, Omaha, NE, USA
| | - Peichao Chen
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cong Huang
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Hongbo Wang
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Anjali Dhar
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Chemistry, Dartmouth College, Hanover, NH, USA
| | - Madelyn Moness
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Davie Shi
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Neurobiology, Northwestern University, Evanston, IL, USA
| | - Savannah Murphy
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Xingeng Zhao
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Siyi Yang
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Isabelle Montoute
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Aneeta Polakkattil
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andie Chung
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Emily Ruiz
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Brianna Carbajal
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Stem cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Alekhya Padavala
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Li Chen
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Guohua Hua
- Department of Obstetrics and Gynecology, Olson Center for Women's Health, University of Nebraska Medical Center, Omaha, NE, USA
| | - Xingcheng Chen
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - John S Davis
- Department of Obstetrics and Gynecology, Olson Center for Women's Health, University of Nebraska Medical Center, Omaha, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Cheng Wang
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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12
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Lee H, Kang J, Lee SH, Lee D, Chung CH, Lee J. Neuroprotective role of Hippo signaling by microtubule stability control in Caenorhabditis elegans. eLife 2025; 13:RP102001. [PMID: 40178516 PMCID: PMC11968107 DOI: 10.7554/elife.102001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025] Open
Abstract
The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in Caenorhabditis elegans. Loss of wts-1/LATS, the core kinase of the Hpo pathway, resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner, the downstream transcriptional co-activator of LATS. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule-stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.
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Affiliation(s)
- Hanee Lee
- Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National UniversitySeoulRepublic of Korea
| | - Junsu Kang
- Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National UniversitySeoulRepublic of Korea
| | - Sang-Hee Lee
- Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National UniversitySeoulRepublic of Korea
| | - Dowoon Lee
- Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National UniversitySeoulRepublic of Korea
| | - Christine H Chung
- Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National UniversitySeoulRepublic of Korea
| | - Junho Lee
- Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National UniversitySeoulRepublic of Korea
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13
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Satoh K, Maeno A, Adachi U, Ishizaka M, Yamada K, Koita R, Nakazawa H, Oikawa S, Fujii R, Furudate H, Kawamura A. Physical constraints on the positions and dimensions of the zebrafish swim bladder by surrounding bones. J Anat 2025; 246:534-543. [PMID: 39556020 PMCID: PMC11911126 DOI: 10.1111/joa.14179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/19/2024] Open
Abstract
Precise regulation of organ size and position is crucial for optimal organ function. Since the swim bladder is primarily responsible for buoyancy in teleosts, early development and subsequent inflation of the swim bladder should be appropriately controlled with the body growth. However, the underlying mechanism remains unclear. In this study, we show that the size and position of the swim bladder are physically constrained by the surrounding bones in zebrafish. Non-invasive micro-CT scanning revealed that the anterior edge of the swim bladder is largely attached to the os suspensorium, which is an ossicle extending medioventrally from the 4th centrum. Additionally, we observed that hoxc6a mutants, which lack the os suspensorium, exhibited an anterior projection of the swim bladder beyond the 4th vertebra. During the swim bladder development, we found that the counterclockwise rotation of the os suspensorium correlates with posterior regression of the swim bladder, suggesting that the os suspensorium pushes the swim bladder posteriorly into its proper position. Furthermore, our results revealed a close association between the posterior region of the swim bladder and the pleural ribs. In hoxaa cluster mutants with additional ribs, the swim bladder expanded posteriorly, accompanied by an enlarged body cavity. Taken together, our results demonstrate the importance of the surrounding bones in the robust regulation of swim bladder size and position in zebrafish.
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Affiliation(s)
- Koumi Satoh
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Akiteru Maeno
- Cell Architecture Laboratory, National Institute of Genetics, Shizuoka, Japan
| | - Urara Adachi
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Mizuki Ishizaka
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Kazuya Yamada
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Rina Koita
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Hidemichi Nakazawa
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Sae Oikawa
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Renka Fujii
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Hiroyuki Furudate
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Akinori Kawamura
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
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14
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Liu OX, Lin LB, Bunk S, Chew T, Wu SK, Motegi F, Low BC. A ZO-2 scaffolding mechanism regulates the Hippo signalling pathway. FEBS J 2025; 292:1587-1601. [PMID: 39462647 DOI: 10.1111/febs.17304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 09/06/2024] [Accepted: 10/08/2024] [Indexed: 10/29/2024]
Abstract
Contact inhibition of proliferation is a critical cell density control mechanism governed by the Hippo signalling pathway. The biochemical signalling underlying cell density-dependent cues regulating Hippo signalling and its downstream effectors, YAP, remains poorly understood. Here, we reveal that the tight junction protein ZO-2 is required for the contact-mediated inhibition of proliferation. We additionally determined that the well-established molecular players of this process, namely Hippo kinase LATS1 and YAP, are regulated by ZO-2 and that the scaffolding function of ZO-2 promotes the interaction with and phosphorylation of YAP by LATS1. Mechanistically, YAP is phosphorylated when ZO-2 brings LATS1 and YAP together via its SH3 and PDZ domains, respectively, subsequently leading to the cytoplasmic retention and inactivation of YAP. In conclusion, we demonstrate that ZO-2 maintains Hippo signalling pathway activation by promoting the stability of LATS1 to inactivate YAP.
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Affiliation(s)
- Olivia Xuan Liu
- Mechanobiology Institute, National University of Singapore, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore
| | | | - Soumya Bunk
- Mechanobiology Institute, National University of Singapore, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Tiweng Chew
- Mechanobiology Institute, National University of Singapore, Singapore
| | - Selwin K Wu
- Mechanobiology Institute, National University of Singapore, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Fumio Motegi
- Mechanobiology Institute, National University of Singapore, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore
- Temasek Life-Sciences Laboratory, Singapore, Singapore
- Institute for Genetic Medicine, Hokkaido University, Japan
| | - Boon Chuan Low
- Mechanobiology Institute, National University of Singapore, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore
- NUS College, National University of Singapore, Singapore
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15
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Church SJ, Pulianmackal AJ, Dixon JA, Loftus LV, Amend SR, Pienta K, Cackowski FC, Buttitta LA. Oncogenic signaling in the Drosophila prostate-like accessory gland activates a pro-tumorigenic program in the absence of proliferation. Dis Model Mech 2025; 18:dmm052001. [PMID: 40304035 PMCID: PMC12067084 DOI: 10.1242/dmm.052001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
Drosophila models for tumorigenesis have revealed conserved mechanisms of signaling involved in mammalian cancer. Many of these models use highly mitotically active Drosophila tissues. Few Drosophila tumorigenesis models use adult tissues, when most cells are terminally differentiated and postmitotic. The Drosophila accessory glands are prostate-like tissues, and a model for prostate tumorigenesis using this tissue has been explored. In this prior model, oncogenic signaling was induced during the proliferative stages of accessory gland development, raising the question of how oncogenic activity impacts the terminally differentiated, postmitotic adult tissue. Here, we show that oncogenic signaling in the adult Drosophila accessory gland leads to activation of a conserved pro-tumorigenic program, similar to that of mitotic tissues, but in the absence of proliferation. In our experiments, oncogenic signaling in the adult gland led to tissue hypertrophy with nuclear anaplasia, in part through endoreduplication. Oncogene-induced gene expression changes in the adult Drosophila prostate-like model overlapped with those in polyploid prostate cancer cells after chemotherapy, which potentially mediate tumor recurrence. Thus, the adult accessory glands provide a useful model for aspects of prostate cancer progression that lack cellular proliferation.
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Affiliation(s)
- S. Jaimian Church
- Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ajai J. Pulianmackal
- Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Joseph A. Dixon
- Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Luke V. Loftus
- Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Sarah R. Amend
- Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Kenneth Pienta
- Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Frank C. Cackowski
- Karmanos Cancer Institute and Wayne State University, Department of Oncology, Detroit, MI 48201, USA
| | - Laura A. Buttitta
- Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
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16
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Scalora N, DeWane G, Drebot Y, Khan AA, Sinha S, Ghosh K, Robinson D, Cogswell P, Bellizzi AM, Snow AN, Breheny P, Chimenti MS, Tanas MR. EHE cell cultures: a platform for mechanistic and therapeutic investigation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.24.644191. [PMID: 40196670 PMCID: PMC11974726 DOI: 10.1101/2025.03.24.644191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Epithelioid hemangioendothelioma (EHE) is a difficult to treat vascular sarcoma defined by TAZ- CAMTA1 or YAP-TFE3 fusion proteins. Human cell lines needed to further understand the pathogenesis of EHE have been lacking. Herein, we describe a method to generate EHE extended primary cell cultures. An integrated multi -omic and functional approach was used to characterize these cultures. The cell cultures, relatively homogenous by single cell RNA-Seq, demonstrated established characteristics of EHE including increased proliferation, anchorage independent growth, as well as the overall gene expression profile and secondary genetic alterations seen in EHE. Whole genome sequencing (WGS) identified links to epigenetic modifying complexes, metabolic processes, and pointed to the importance of the extracellular matrix (ECM) in these tumors. Bulk RNA-Seq demonstrated upregulation of pathways including PI3K-Akt signaling, ECM/ECM receptor interaction, and the Hippo signaling pathway. Development of these extended primary cell cultures allowed for single-cell profiling which demonstrated different cell compartments within the cultures. Furthermore, the cultures served as a therapeutic platform to test the efficacy of TEAD inhibitors in vitro . Overall, the development of EHE primary cell cultures will aid in the mechanistic understanding of this sarcoma and serve as a model system to test new therapeutic approaches.
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17
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Wang DH, He DW, Lv TT, Zhang XK, Li ZJ, Wang ZY. Estrogen receptor α suppresses hepatocellular carcinoma by restricting M2 macrophage infiltration through the YAP-CCL2 axis. BMC Cancer 2025; 25:550. [PMID: 40148834 PMCID: PMC11948847 DOI: 10.1186/s12885-025-13676-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 02/06/2025] [Indexed: 03/29/2025] Open
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with significant differences in incidence and outcomes between men and women. Estrogen receptor alpha (ERα) expression is associated with sex-based differences and poor prognostic outcomes in HCC. However, the detailed function of ERα in the tumor microenvironment of HCC remains unclear. METHODS Bioinformatics analysis of differentially expressed genes in HCC samples was performed from publicly available databases, and ERα was selected. The function of ERα was examined in the cell experiments. A co-culture system was built to study function of ERα-treated liver cells on macrophages in vitro. The precise mechanism was determined using quantitative real-time PCR, western blotting, immunohistochemistry, mass spectrometry, co-immunoprecipitation, and dual-luciferase reporter assay. RESULTS ERα played an important role in the pathogenesis of sexual dimorphism in HCC. ERα mainly acted on macrophages in the tumor microenvironment (TME) of HCC and reduced M2 macrophage infiltration through CCL2. By acting on NF2 and 14-3-3theta, ERα enhanced YAP phosphorylation and attenuated the nuclear translocation of YAP, thereby suppressing CCL2 expression. It also acted as a transcription factor that regulated CCL2 expression at the transcriptional level. CONCLUSION ERα/YAP/CCL2 signaling reduced M2 macrophages infiltration to inhibit HCC progression, revealing the effect of ERα in cancer cells on immune cells in HCC microenvironment.
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Affiliation(s)
- De-Hua Wang
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, P. R. China
- Division of Liver Disease, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei, 050023, P. R. China
| | - Dong-Wei He
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, P. R. China
| | - Ting-Ting Lv
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, P. R. China
| | - Xiao-Kuan Zhang
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, P. R. China
| | - Zi-Jie Li
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, P. R. China
| | - Zhi-Yu Wang
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, P. R. China.
- , 12, Jiankang Road, Chang'an District, Shijiazhuang City, Hebei Province, China.
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18
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Meng Y, Ge J, Zhou C, Ma H, Chen C, Zhou Y, Hu X, Xu Y, Wang X, Shi G, Yu W, Zhang J. Elevated VRK1 levels after androgen deprivation therapy promote prostate cancer progression by upregulating YAP1 expression. J Cancer Res Clin Oncol 2025; 151:116. [PMID: 40111564 PMCID: PMC11926012 DOI: 10.1007/s00432-025-06168-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
PURPOSE Vaccinia-related kinase 1 (VRK1) is a serine-threonine kinase involved in the proliferation and migration of various cancer cells. However, its role in prostate cancer (PCa), particularly in the development of therapeutic resistance, remains unclear. METHODS We established an androgen-independent PCa cell line derived from LNCaP prostate cancer cells and conducted transcriptome and proteome sequencing together with bioinformatic analyses of large clinical sample databases to investigate the potential role of VRK1 in PCa progression. The correlation between VRK1 and androgen receptor (AR) signaling was evaluated under simulated clinical treatment conditions. The effects of VRK1 on cell proliferation were assessed in vitro and in vivo using Cell Counting Kit-8 and colony formation assays. Additionally, proteome and transcriptome sequencing, combined with rescue experiments were performed to explore VRK1-regulated signaling pathways related to cell proliferation and therapeutic resistance. RESULTS VRK1 expression was elevated during the progression of androgen-dependent prostate cancer to castration-resistant prostate cancer under therapeutic conditions, and high VRK1 expression was associated with a poor prognosis in patients with PCa. VRK1 was regulated by AR signaling, and its silencing suppressed PCa cell proliferation both in vitro and in vivo. VRK1 drove cell proliferation and therapeutic resistance in PCa by modulating yes-associated protein 1 (YAP1). CONCLUSIONS VRK1 serves as a prognostic marker in PCa, regulated by AR signaling. VRK1 depletion inhibited cell proliferation both in vitro and in vivo, while elevated VRK1 upregulated YAP1, promoting cell proliferation and therapeutic resistance.
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MESH Headings
- Humans
- Male
- YAP-Signaling Proteins
- Disease Progression
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Adaptor Proteins, Signal Transducing/biosynthesis
- Animals
- Cell Proliferation
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Mice
- Protein Serine-Threonine Kinases/metabolism
- Protein Serine-Threonine Kinases/genetics
- Prostatic Neoplasms/pathology
- Prostatic Neoplasms/genetics
- Prostatic Neoplasms/metabolism
- Prostatic Neoplasms/drug therapy
- Up-Regulation
- Receptors, Androgen/metabolism
- Intracellular Signaling Peptides and Proteins/metabolism
- Intracellular Signaling Peptides and Proteins/genetics
- Gene Expression Regulation, Neoplastic
- Cell Line, Tumor
- Prostatic Neoplasms, Castration-Resistant/pathology
- Prostatic Neoplasms, Castration-Resistant/genetics
- Prostatic Neoplasms, Castration-Resistant/metabolism
- Prostatic Neoplasms, Castration-Resistant/drug therapy
- Prognosis
- Mice, Nude
- Androgen Antagonists/pharmacology
- Signal Transduction
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Yibo Meng
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Jianchao Ge
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Cheng Zhou
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Hangbin Ma
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Chenchen Chen
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Yinghao Zhou
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Xuetao Hu
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Yaozong Xu
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Xilong Wang
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China
| | - Guowei Shi
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China.
| | - Wandong Yu
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China.
| | - Jun Zhang
- Department of Urology, The Fifth People'S Hospital of Shanghai, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, People's Republic of China.
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19
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ZHANG P, ZHAN Y. [Research Advances in Targeting the YAP/TAZ Signaling Pathway
to Improve Cancer Immunotherapy]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2025; 28:221-229. [PMID: 40210482 PMCID: PMC11986679 DOI: 10.3779/j.issn.1009-3419.2025.102.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Indexed: 04/12/2025]
Abstract
Despite the groundbreaking advances in cancer immunotherapy achieved by immune checkpoint inhibitors (ICIs), their efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key effectors of the Hippo signaling pathway, play pivotal roles in tumor immune evasion. They directly regulate the expression of immune checkpoints, mediate the formation of an immunosuppressive microenvironment, inhibit T cell function, and interact with other signaling pathways to promote immune escape. Diverse strategies targeting YAP/TAZ have been developed, including direct inhibition, modulation of upstream regulators, and suppression of downstream target genes. Preclinical studies have demonstrated that combining YAP/TAZ inhibition with ICIs significantly enhances therapeutic efficacy across various tumor models. This review summarizes recent advances in understanding the role of YAP/TAZ in immune evasion within the TME and explores the potential of targeting this pathway to improve immunotherapy outcomes. Furthermore, it discusses the translational value of combination therapies based on YAP/TAZ inhibition, providing a theoretical framework and practical guidance for the development of innovative immunotherapeutic strategies and precision medicine approaches.
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20
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Li X, Cho YS, Han Y, Zhou M, Liu Y, Yang Y, Zhuo S, Jiang J. The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2. J Biol Chem 2025; 301:108430. [PMID: 40120683 PMCID: PMC12018991 DOI: 10.1016/j.jbc.2025.108430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 03/07/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025] Open
Abstract
The prevailing view in the cancer field is that Hippo (Hpo) signaling pathway functions as a tumor suppressor pathway by blocking the oncogenic potential of the pathway effectors Yes1-associated transcriptional regulator (YAP)/transcriptional coactivator with PDZ-binding motif. However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCCs). We find that, in addition to inhibiting hypoxia-inducible factor 2α, a major oncogenic driver in Von Hippel-Lindau-/- ccRCC, YAP also blocks nuclear factor κB (NF-κB) signaling in ccRCC to inhibit cancer cell growth under conditions where hypoxia-inducible factor 2α is dispensable. Mechanistically, YAP inhibits the expression of Zinc fingers and homeoboxes 2 (ZHX2), a Von Hippel-Lindau substrate and critical cofactor of NF-κB in ccRCC. Furthermore, YAP competes with ZHX2 for binding to the NF-κB subunit p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and the NF-κB subunit p65, leading to diminished NF-κB target gene expression. Pharmacological inhibition of Hpo kinase blocked NF-κB transcriptional program and suppressed ccRCC cell growth, which can be rescued by overexpression of ZHX2 or p65. Our study uncovers a crosstalk between the Hpo and NF-κB/ZHX2 pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hpo pathway may provide a therapeutical opportunity for ccRCC treatment.
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Affiliation(s)
- Xu Li
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
| | - Yong Suk Cho
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Math and Sciences, Tarrant County College-NE Campus, Hurst, Texas, USA
| | - Yuhong Han
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Mengmeng Zhou
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Boston, Massachusetts, USA; Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Boston, Massachusetts, USA; Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA
| | - Shu Zhuo
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jin Jiang
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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21
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Lu Y, Yan Z, Sun J, Wang C, Xu L, Lyu X, Wang X, Lou J, Huang H, Meng L, Zhao Y. Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo. J Med Chem 2025; 68:5616-5640. [PMID: 39804031 DOI: 10.1021/acs.jmedchem.4c02884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
Genetic mutations in components of the Hippo pathway frequently lead to the aberrant activation of TEADs, which is often associated with cancer. Consequently, TEADs have been actively pursued as therapeutic targets for diseases driven by TEAD overactivation. In this study, we report two series of TEAD PROTACs based on CRBN binders and VHL binders. Both series yielded potent TEAD degraders, including 19 and 40 (H122), which induced TEAD1 degradation with DC50 < 10 nM. Mechanistic studies demonstrated that the degradation of TEAD1 induced by 40 relied on CRBN binding, TEAD1 binding, E3 ligase activity, and a functional proteasome. RNA-seq analyses indicated that 40 significantly downregulated the expression of Myc target genes, as highlighted by GSEA analysis. More importantly, 40 exhibited robust antitumor efficacy in the MSTO-211H mouse xenograft model. Collectively, our results suggest that TEAD PROTACs have therapeutic potential for the treatment of cancers associated with TEAD overactivation.
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Affiliation(s)
- Yuhang Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Ziqin Yan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
| | - Jiaqi Sun
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Chenxu Wang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lan Xu
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xilin Lyu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
| | - Xiancheng Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Jianfeng Lou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - He Huang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Linghua Meng
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Yujun Zhao
- Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia Province 750004, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
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22
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Chen X, Ji X, Lao Z, Pan B, Qian Y, Yang W. Role of YAP/TAZ in bone diseases: A transductor from mechanics to biology. J Orthop Translat 2025; 51:13-23. [PMID: 39902099 PMCID: PMC11787699 DOI: 10.1016/j.jot.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/24/2024] [Accepted: 12/09/2024] [Indexed: 02/05/2025] Open
Abstract
Wolff's Law and the Mechanostat Theory elucidate how bone tissues detect and convert mechanical stimuli into biological signals, crucial for maintaining bone equilibrium. Abnormal mechanics can lead to diseases such as osteoporosis, osteoarthritis, and nonunion fractures. However, the detailed molecular mechanisms by which mechanical cues are transformed into biological responses in bone remain underexplored. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key regulators of bone homeostasis, are instrumental in this process. Emerging research highlights bone cells' ability to sense various mechanical stimuli and relay these signals intracellularly. YAP/TAZ are central in receiving these mechanical cues and converting them into signals that influence bone cell behavior. Abnormal YAP/TAZ activity is linked to several bone pathologies, positioning these proteins as promising targets for new treatments. Thus, this review aims to provide an in-depth examination of YAP/TAZ's critical role in the interpretation of mechanical stimuli to biological signals, with a special emphasis on their involvement in bone cell mechanosensing, mechanotransduction, and mechanoresponse. The translational potential of this article: Clinically, appropriate stress stimulation promotes fracture healing, while bed rest can lead to disuse osteoporosis and excessive stress can cause osteoarthritis or bone spurs. Recent advancements in the understanding of YAP/TAZ-mediated mechanobiological signal transduction in bone diseases have been significant, yet many aspects remain unknown. This systematic review summarizes current research progress, identifies unaddressed areas, and highlights potential future research directions. Advancements in this field facilitate a deeper understanding of the molecular mechanisms underlying bone mechanics regulation and underscore the potential of YAP/TAZ as therapeutic targets for bone diseases such as fractures, osteoporosis, and osteoarthritis.
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Affiliation(s)
- Xin Chen
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, China
| | - Xing Ji
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Zhaobai Lao
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, China
| | - Bin Pan
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, China
| | - Yu Qian
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, China
| | - Wanlei Yang
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, China
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Guo P, Wan S, Guan KL. The Hippo pathway: Organ size control and beyond. Pharmacol Rev 2025; 77:100031. [PMID: 40148032 DOI: 10.1016/j.pharmr.2024.100031] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 12/17/2024] [Indexed: 03/29/2025] Open
Abstract
The Hippo signaling pathway is a highly conserved signaling network for controlling organ size, tissue homeostasis, and regeneration. It integrates a wide range of intracellular and extracellular signals, such as cellular energy status, cell density, hormonal signals, and mechanical cues, to modulate the activity of YAP/TAZ transcriptional coactivators. A key aspect of Hippo pathway regulation involves its spatial organization at the plasma membrane, where upstream regulators localize to specific membrane subdomains to regulate the assembly and activation of the pathway components. This spatial organization is critical for the precise control of Hippo signaling, as it dictates the dynamic interactions between pathway components and their regulators. Recent studies have also uncovered the role of biomolecular condensation in regulating Hippo signaling, adding complexity to its control mechanisms. Dysregulation of the Hippo pathway is implicated in various pathological conditions, particularly cancer, where alterations in YAP/TAZ activity contribute to tumorigenesis and drug resistance. Therapeutic strategies targeting the Hippo pathway have shown promise in both cancer treatment, by inhibiting YAP/TAZ signaling, and regenerative medicine, by enhancing YAP/TAZ activity to promote tissue repair. The development of small molecule inhibitors targeting the YAP-TEAD interaction and other upstream regulators offers new avenues for therapeutic intervention. SIGNIFICANCE STATEMENT: The Hippo signaling pathway is a key regulator of organ size, tissue homeostasis, and regeneration, with its dysregulation linked to diseases such as cancer. Understanding this pathway opens new possibilities for therapeutic approaches in regenerative medicine and oncology, with the potential to translate basic research into improved clinical outcomes.
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Affiliation(s)
- Pengfei Guo
- School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
| | - Sicheng Wan
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Kun-Liang Guan
- School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
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Li B, Di G, Ge H, Song P, Han W, Sun H, Wang D, Chen P, Wang Y. Aquaporin-5 facilitates liver regeneration following hepatectomy via ROS/GSDMD pathway. Cell Signal 2025; 127:111602. [PMID: 39814248 DOI: 10.1016/j.cellsig.2025.111602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/01/2025] [Accepted: 01/09/2025] [Indexed: 01/18/2025]
Abstract
During the proliferative phase of liver regeneration, insufficient regulation of hepatocyte hydrogen peroxide (H2O2) overproduction can result in oxidative stress and hepatocyte death. This study aims to investigate the influence of Aquaporin 5 (Aqp5) on liver regeneration by evaluating its role in reactive oxygen species (ROS) generation and NLRP3-GSDMD-mediated pyroptosis. A 70 % partial hepatectomy (PHx) model was established in Aqp5-/- mice to evaluate the pathological changes in the liver. Reactive oxygen species (ROS) production was assessed using a dichlorodihydrofluorescein diacetate (DCFH-DA) assay. Aqp5 deficiency significantly increased ROS production, the number of TUNEL-positive cells, and disrupted mitochondrial membrane potential in the liver of Aqp5-deficient mice. The impact of Aqp5 on ROS/NLRP3/Gasdermin-D (GSDMD)-mediated pyroptosis was examined through the administration of N-acetyl-L-cysteine (NAC, an ROS scavenger) or disulfiram (DSF, a GSDMD inhibitor). In Aqp5-deficient mice, the regenerative liver exhibited increased expression of NLRP3, enhanced activation of caspase-1 and GSDMD, as well as elevated secretion of IL-1β. Treatment with DSF significantly attenuated GSDMD-mediated pyroptosis triggered by Aqp5 deficiency in the regenerating liver. Furthermore, the administration of NAC to Aqp5-deficient mice resulted in a reduction in the expression levels of NLRP3, the activity levels of caspase-1 and GSDMD, as well as the release of IL-1β. Our findings indicate that the deficiency of Aqp5 facilitates GSDMD activation through the production of ROS. The suppression of ROS or inhibition of GSDMD significantly alleviates the damage and pyroptosis observed in Aqp5-deficient regenerative liver.
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Affiliation(s)
- Bin Li
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China
| | - Guohu Di
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China.
| | - Huanhuan Ge
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China
| | - Peirong Song
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China
| | - Wenshuo Han
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China
| | - Hetong Sun
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China
| | - Dianqiang Wang
- Qingdao Aier Eye Hospital, Qingdao, Shandong Province, 266400, China
| | - Peng Chen
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China; Department of Emergency Medicine, Qingdao Eighth People's Hospital, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong Province 266071, China.
| | - Ye Wang
- Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), No. 127th, South Siliu Road, Qingdao, Shandong 266042, China.
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25
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Yang Y, Xue Z, Lai J, Zhang J, Pang C, Zhong J, Kuang Z, Zou B, Liu Y, Sun L. Kibra knockdown inhibits the aberrant Hippo pathway, suppresses renal cyst formation and ameliorates renal fibrosis in nphp1 KO mice. Clin Transl Med 2025; 15:e70245. [PMID: 39995111 PMCID: PMC11850762 DOI: 10.1002/ctm2.70245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 01/11/2025] [Accepted: 02/13/2025] [Indexed: 02/26/2025] Open
Abstract
INTRODUCTION Nephronophthisis (NPH) is an autosomal recessive interstitial cystic kidney disease, which is the most common genetic cause of end-stage renal disease (ESRD) in childhood. The Hippo pathway is regulated by the cilium and has been suggested to be linked to NPH. The aim of the study was to investigate the involvement of Hippo pathway in the pathogenesis of nphp1 defect-associated NPH (NPH1). METHOD Nphp1 knockout (nphp1KO) Madin-Darby Canine Kidney (MDCK) cells and nphp1KO C57BL/6J mice were generated via CRISPR gene editing strategy. The siRNAs targeting Kibra, MST1 and LATS1 were designed. An AAV9 vector was designed for Kibra knockdown. The expression and phosphorylation of core Hippo pathway molecules were evaluated. Pathological renal changes were evaluated via light microscopy respectively with haematoxylin-eosin and Masson staining. RESULTS In nphp1KO MDCK cells, nphp1KO mice and NPH1 patients' kidneys, Kibra, p-MST1/2, p-LATS and p-YAP exhibited a notable increase in levels, with an even greater elevation observed in renal cyst cells, indicating the Hippo pathway activated in these nphp1-deficient contexts. Nphp1 re-expression reversed the Hippo pathway activation in cells, indicating that the Hippo pathway activation is related to nphp1 deficiency in vitro. Meanwhile, in vitro, MST1 knockdown downregulated LATS1 and YAP phosphorylation, LATS1 knockdown downregulated YAP phosphorylation, suggesting the activation of the canonical Hippo pathway in nphp1-deficient contexts. Knockdown of the upstream regulator Kibra inhibited the Hippo pathway activation in both nphp1KO MDCK cells and mice. Following Kibra knockdown, the organisation of nphp1KO MDCK cells became more compact, the intensity of the actin fibres increased. Besides, decreased renal fibrosis and cyst formation were observed in nphp1KO mice. CONCLUSIONS The canonical Hippo pathway is aberrantly activated in nphp1-deficient conditions. Kibra may serve as a crucial upstream regulator of nphp1 deficiency-related Hippo pathway activation. Kibra upregulation and activation of the Hippo pathway are involved in the pathogenesis of NPH1. KEY POINTS Canonical Hippo pathway activated in nphp1-deficient disease models and patients. Kibra was a key upstream molecule in regulating the activation of canonical Hippo pathway in nphp1-deficient disease models and patients and closely related to renal cyst formation and fibrosis in nphp1KO mice.
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Affiliation(s)
- Yichen Yang
- Department of PediatricsNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Zhihe Xue
- Department of PediatricsNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Jiayong Lai
- Department of PediatricsNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Jinglan Zhang
- Department of PediatricsNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Changmiao Pang
- Department of PediatricsNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Jinglin Zhong
- Department of PediatricsShenzhen Maternity and Child Healthcare HospitalShenzhenChina
| | - Zhanpeng Kuang
- Department of PediatricsNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Baojuan Zou
- Department of PediatricsNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Yaqing Liu
- Department of PediatricsThe First Affiliated Hospital, Gannan Medical UniversityGanzhouChina
| | - Liangzhong Sun
- Department of PediatricsNanfang Hospital, Southern Medical UniversityGuangzhouChina
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Dawson LE, Sekar A, Fulford AD, Lambert RI, Burgess HS, Ribeiro PS. The deubiquitylating enzyme Fat facets promotes Fat signalling and restricts tissue growth. Nat Commun 2025; 16:1938. [PMID: 39994229 PMCID: PMC11850632 DOI: 10.1038/s41467-025-57164-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 02/13/2025] [Indexed: 02/26/2025] Open
Abstract
Tissue growth is regulated by many signals, including polarity cues. The Hippo signalling pathway restricts tissue growth and receives inputs from the planar cell polarity-controlling Fat signalling pathway. The atypical cadherin Fat restricts growth via several mechanisms that ultimately control the activity of the pro-growth transcriptional co-activator Yorkie. Fat signalling activates the Yorkie inhibitory kinase Warts, and modulates the function of the FERM protein Expanded, which promotes Hippo signalling and also directly inhibits Yorkie. Although several Fat pathway activity modulators are known to be involved in ubiquitylation, the role of this post-translational modification in the pathway remains unclear. Moreover, no deubiquitylating enzymes have been described in this pathway. Here, using in vivo RNAi screening, we identify the deubiquitylating enzyme Fat facets as a positive regulator of Fat signalling with roles in tissue growth control. Fat facets interacts genetically and physically with Fat signalling components and regulates Yorkie target gene expression. Thus, we uncover a role for reversible ubiquitylation in the control of Fat signalling and tissue growth regulation.
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Affiliation(s)
- Lauren E Dawson
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London, UK
| | - Aashika Sekar
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK
- Apoptosis and Proliferation Control Laboratory, The Francis Crick Institute, 1 Midland Road, London, UK
| | - Alexander D Fulford
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Rachel I Lambert
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK
| | - Hannah S Burgess
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK
| | - Paulo S Ribeiro
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK.
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Paul S, Hagenbeek TJ, Tremblay J, Kameswaran V, Ong C, Liu C, Guarnaccia AD, Mondo JA, Hsu PL, Kljavin NM, Czech B, Smola J, Nguyen DAH, Lacap JA, Pham TH, Liang Y, Blake RA, Gerosa L, Grimmer M, Xie S, Daniel B, Yao X, Dey A. Cooperation between the Hippo and MAPK pathway activation drives acquired resistance to TEAD inhibition. Nat Commun 2025; 16:1743. [PMID: 39966375 PMCID: PMC11836325 DOI: 10.1038/s41467-025-56634-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 01/26/2025] [Indexed: 02/20/2025] Open
Abstract
TEAD (transcriptional enhanced associate domain) transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. Targeted therapy leads to the emergence of resistance and the underlying mechanism of resistance to TEAD inhibition in cancers is less characterized. We uncover that upregulation of the AP-1 (activator protein-1) transcription factors, along with restored YAP (yes-associated protein) and TEAD activity, drives resistance to GNE-7883, a pan-TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP-TEAD binding and attenuates FOSL1 (FOS like 1) activity. TEAD inhibitor resistant cells restore YAP and TEAD chromatin occupancy, acquire additional FOSL1 binding and exhibit increased MAPK (mitogen-activated protein kinase) pathway activity. FOSL1 is required for the chromatin binding of YAP and TEAD. This study describes a clinically relevant interplay between the Hippo and MAPK pathway and highlights the key role of MAPK pathway inhibitors in mitigating resistance to TEAD inhibition in Hippo pathway dependent cancers.
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Affiliation(s)
- Sayantanee Paul
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA
| | - Thijs J Hagenbeek
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA
| | - Julien Tremblay
- gRED Computational Sciences, Genentech Inc, South San Francisco, CA, USA
| | - Vasumathi Kameswaran
- Department of Proteomic and Genomic Technologies, Genentech Inc, South San Francisco, CA, USA
| | - Christy Ong
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA
| | - Chad Liu
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA
| | - Alissa D Guarnaccia
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA
- Department of Proteomic and Genomic Technologies, Genentech Inc, South San Francisco, CA, USA
| | - James A Mondo
- Roche Informatics, Hoffman-La Roche Canada, Mississauga, ON, Canada
| | - Peter L Hsu
- Department of Structural Biology, Genentech Inc, South San Francisco, CA, USA
| | - Noelyn M Kljavin
- Department of Research Oncology, Genentech Inc, South San Francisco, CA, USA
| | - Bartosz Czech
- Roche Global IT Solution Centre, Roche, Warsaw, Poland
| | - Janina Smola
- Roche Global IT Solution Centre, Roche, Warsaw, Poland
| | - Dieu An H Nguyen
- Department of Early Discovery Biochemistry, Genentech Inc, South San Francisco, CA, USA
| | - Jennifer A Lacap
- Department of Translational Oncology, Genentech Inc, South San Francisco, CA, USA
| | - Trang H Pham
- Department of Translational Medicine, Genentech Inc, South San Francisco, CA, USA
| | - Yuxin Liang
- Department of Proteomic and Genomic Technologies, Genentech Inc, South San Francisco, CA, USA
| | - Robert A Blake
- Department of Biochemical and Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA
| | - Luca Gerosa
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA
- gRED Computational Sciences, Genentech Inc, South San Francisco, CA, USA
| | - Matthew Grimmer
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA
- gRED Computational Sciences, Genentech Inc, South San Francisco, CA, USA
| | - Shiqi Xie
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA
| | - Bence Daniel
- Department of Proteomic and Genomic Technologies, Genentech Inc, South San Francisco, CA, USA
| | - Xiaosai Yao
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA.
- gRED Computational Sciences, Genentech Inc, South San Francisco, CA, USA.
| | - Anwesha Dey
- Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA.
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Hrncir HR, Goodloe B, Bombin S, Hogan CB, Jadi O, Gracz AD. Sox9 inhibits Activin A to promote biliary maturation and branching morphogenesis. Nat Commun 2025; 16:1667. [PMID: 39955269 PMCID: PMC11830073 DOI: 10.1038/s41467-025-56813-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 01/31/2025] [Indexed: 02/17/2025] Open
Abstract
Intrahepatic bile duct (IHBD) development produces a morphologically heterogeneous network of large "ducts" and small "ductules" by adulthood. IHBD formation is closely linked to developmental specification of biliary epithelial cells (BECs) starting as early as E13.5, but mechanisms regulating differential IHBD morphology remain poorly understood. Here, we show that duct and ductule development has distinct genetic requirements, with Sox9 required to form the developmental precursors to peripheral ductules in adult livers. By optimizing large-volume IHBD imaging, we find that IHBDs emerge as a homogeneous webbed structure by E15.5 and undergo morphological maturation through 2 weeks of age. Developmental knockout of Sox9 leads to decreased postnatal branching morphogenesis, resulting in adult IHBDs with normal ducts but significantly fewer ductules. In the absence of Sox9, BECs fail to mature and exhibit elevated TGF-β signaling and Activin A. Exogenous Activin A is sufficient to induce developmental gene expression and morphological defects in wild-type BEC organoids, while early postnatal inhibition of Activin A in vivo rescues IHBD morphogenesis in the absence of Sox9. Our data demonstrate that proper IHBD architecture relies on inhibition of Activin A by Sox9 to promote ductule morphogenesis, defining regulatory mechanisms underlying morphological heterogeneity.
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Affiliation(s)
- Hannah R Hrncir
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, GA, USA
| | - Brianna Goodloe
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA
| | - Sergei Bombin
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA
| | - Connor B Hogan
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA
| | - Othmane Jadi
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Adam D Gracz
- Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA, USA.
- Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, GA, USA.
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Li X, Cho YS, Han Y, Zhou M, Liu Y, Yang Y, Zhuo S, Jiang J. The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.06.21.600079. [PMID: 38979373 PMCID: PMC11230290 DOI: 10.1101/2024.06.21.600079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
The prevailing view in the cancer field is that Hippo signaling pathway functions as a tumor suppressor pathway by blocking the oncogenic potential of the pathway effectors Yes1 associated transcriptional regulator (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCC). We find that, in additional to inhibiting hypoxia-inducible factor 2α (HIF2α), a major oncogenic driver in Von Hippel-Lindau (VHL)-/- ccRCC, YAP also blocks nuclear factor κB (NF-κB ) signaling in ccRCC to inhibit cancer cell growth under conditions where HIF2α is dispensable. Mechanistically, YAP inhibits the expression of Zinc fingers and homeoboxes 2 (ZHX2), a VHL substrate and critical co-factor of NF-κB in ccRCC. Furthermore, YAP competes with ZHX2 for binding to the NF-κB subunit p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and the NF-κB subunit p65, leading to diminished NF-κB target gene expression. Pharmacological inhibition of Hippo kinase blocked NF-κB transcriptional program and suppressed ccRCC cancer cell growth, which can be rescued by overexpression of ZHX2 or p65. Our study uncovers a crosstalk between the Hippo and NF-κB/ZHX2 pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hippo pathway may provide a therapeutical opportunity for ccRCC treatment.
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Affiliation(s)
- Xu Li
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yong Suk Cho
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Math and Sciences, Tarrant County College-NE Campus, 828 W Harwood Rd, Hurst, TX 76054, USA
| | - Yuhong Han
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Mengmeng Zhou
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave. Boston, MA 02215, USA
- Harvard Stem Cell Institute, 188 Longwood Ave. Boston, MA 02215, USA
- Dana-Farber/Harvard Cancer Center, 188 Longwood Ave. Boston, MA 02215, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave. Boston, MA 02215, USA
- Harvard Stem Cell Institute, 188 Longwood Ave. Boston, MA 02215, USA
- Dana-Farber/Harvard Cancer Center, 188 Longwood Ave. Boston, MA 02215, USA
| | - Shu Zhuo
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jin Jiang
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Peng Y, Yuan Q, Zhou S, Gan J, Shen Z, Xia X, Jiang Y, Chen Q, Yuan Y, He G, Wei Q, Feng X. FAK mediates mechanical signaling to maintain epithelial homeostasis through YAP/TAZ-TEADs. Histochem Cell Biol 2025; 163:31. [PMID: 39918604 DOI: 10.1007/s00418-025-02360-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2025] [Indexed: 02/09/2025]
Abstract
Epithelial homeostasis ensures that the epithelium can perform its normal physiological functions. Mechanical signaling response through integrin-mediated adhesions of the basement membrane (BM) is crucial for maintaining epithelial homeostasis. The essential mechanosensors YAP and the paralog TAZ (YAP/TAZ) have been shown to play a critical role in epithelial homeostasis, but the key regulator that mediates mechanical signaling to YAP/TAZ in maintaining epithelial homeostasis has not been fully understood. In this study, we noticed that mechanical signals correlated with YAP/TAZ activation and basal state maintenance in epithelial stem/progenitor cells through immunohistochemistry. Subsequently, we found that inhibition of focal adhesion kinase (FAK) suppressed YAP/TAZ activation in the human keratinocyte line HaCaT cells. Furthermore, inhibition of the interaction between YAP/TAZ and the transcriptional enhanced associate domains (TEADs) resulted in the differentiation of HaCaT cells. Finally, we used primary mouse epithelial cells to reconstruct the epithelium in vitro and found that FAK inhibition led to both a reduction in YAP/TAZ activity and an increase of differentiation in the basal layer cells. In conclusion, our findings reveal that FAK mediates mechanical signaling to maintain epithelial homeostasis via YAP/TAZ-TEADs.
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Affiliation(s)
- Yang Peng
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Qiuyun Yuan
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Shuting Zhou
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Jianguo Gan
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Zhengzhong Shen
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Xiaoqiang Xia
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yuchen Jiang
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Qianming Chen
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Affiliated Stomatology Hospital, Zhejiang University School of Stomatology, Hangzhou, 310000, China
| | - Yao Yuan
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Gu He
- Department of Dermatology and Venerology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qiang Wei
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials and Engineering, Sichuan University, Chengdu, 610065, China.
| | - Xiaodong Feng
- State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases and Frontier Innovation Center for Dental Medicine Plus and Research Unit of Oral Carcinogenesis and Management and Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
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Wang S, Wu X, Bi W, Xu J, Hou L, Li G, Pan Y, Zhang H, Li M, Du S, Zhang M, Liu D, Jin S, Shi X, Tian Y, Shuai J, Plikus MV, Song M, Zhou Z, Yu L, Lv C, Yu Z. ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3. Nat Commun 2025; 16:1406. [PMID: 39915446 PMCID: PMC11802746 DOI: 10.1038/s41467-025-56444-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 01/18/2025] [Indexed: 02/09/2025] Open
Abstract
Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics.
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Affiliation(s)
- Shiyang Wang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Xi Wu
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Wenxin Bi
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Jiuzhi Xu
- Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Liyuan Hou
- Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Guilin Li
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yuwei Pan
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Hanfu Zhang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Mengzhen Li
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Sujuan Du
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Mingxin Zhang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Di Liu
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Shuiling Jin
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaojing Shi
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Yuhua Tian
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jianwei Shuai
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, China
| | - Maksim V Plikus
- Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA
| | - Moshi Song
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lu Yu
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China.
| | - Cong Lv
- Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing, China.
| | - Zhengquan Yu
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China.
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Allen RS, Seifert AW. Spiny mice (Acomys) have evolved cellular features to support regenerative healing. Ann N Y Acad Sci 2025; 1544:5-26. [PMID: 39805008 PMCID: PMC11830558 DOI: 10.1111/nyas.15281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Spiny mice (Acomys spp.) are warm-blooded (homeothermic) vertebrates whose ability to restore missing tissue through regenerative healing has coincided with the evolution of unique cellular and physiological adaptations across different tissue types. This review seeks to explore how these bizarre rodents deploy unique or altered injury response mechanisms to either enhance tissue repair or fully regenerate excised tissue compared to closely related, scar-forming mammals. First, we examine overall trends in healing Acomys tissues, including the cellular stress response, the ability to activate and maintain cell cycle progression, and the expression of certain features in reproductive adults that are normally associated with embryos. Second, we focus on specific cell types that exhibit precisely regulated proliferation to restore missing tissue. While Acomys utilize many of the same cell types involved in scar formation, these cells exhibit divergent activation profiles during regenerative healing. Considered together, current lines of evidence support sustained deployment of proregenerative pathways in conjunction with transient activation of fibrotic pathways to facilitate regeneration and improve tissue repair in Acomys.
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Affiliation(s)
- Robyn S. Allen
- Department of Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Ashley W. Seifert
- Department of Biology, University of Kentucky, Lexington, Kentucky, USA
- The Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, Kentucky, USA
- Department of Veterinary Anatomy and Physiology, University of Nairobi, Nairobi, Kenya
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35
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Jia Q, Wang H, Bi B, Han X, Jia Y, Zhang L, Fang L, Thakur A, Cheng JC. Amphiregulin Downregulates E-cadherin Expression by Activating YAP/Egr-1/Slug Signaling in SKOV3 Human Ovarian Cancer Cells. Reprod Sci 2025; 32:404-416. [PMID: 39138796 DOI: 10.1007/s43032-024-01673-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 08/01/2024] [Indexed: 08/15/2024]
Abstract
Amphiregulin (AREG) stimulates human epithelial ovarian cancer (EOC) cell invasion by downregulating E-cadherin expression. YAP is a transcriptional cofactor that has been shown to regulate tumorigenesis. This study aimed to examine whether AREG activates YAP in EOC cells and explore the roles of YAP in AREG-induced downregulation of E-cadherin and cell invasion. Analysis of the Cancer Genome Atlas (TCGA) showed that upregulation of AREG and EGFR were associated with poor survival in human EOC. Treatment of SKOV3 human EOC cells with AREG induced the activation of YAP. In addition, AREG downregulated E-cadherin, upregulated Egr-1 and Slug, and stimulated cell invasion. Using gain- and loss-of-function approaches, we showed that YAP was required for the AREG-upregulated Egr-1 and Slug expression. Furthermore, YAP was also involved in AREG-induced downregulation of E-cadherin and cell invasion. This study provides evidence that AREG stimulates human EOC cell invasion by downregulating E-cadherin expression through the YAP/Egr-1/Slug signaling.
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Affiliation(s)
- Qiongqiong Jia
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Hailong Wang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Beibei Bi
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyu Han
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuanyuan Jia
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lingling Zhang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lanlan Fang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Avinash Thakur
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Jung-Chien Cheng
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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36
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Zhou Y, Wu H, Wang Q, Ma B, Sun J, Wang G. DNA Methylation Regulatory Axis miR-29b-3p/DNMT3B Regulates Liver Regeneration Process by Altering LATS1. J Cell Mol Med 2025; 29:e70405. [PMID: 39937032 PMCID: PMC11816157 DOI: 10.1111/jcmm.70405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 01/12/2025] [Accepted: 01/20/2025] [Indexed: 02/13/2025] Open
Abstract
DNA methylation is a crucial epigenetic alteration involved in diverse biological processes and diseases. Hippo signalling pathway is a key signalling regulatory network in the growth and development of tissues and organs. Nevertheless, the precise role of DNA methylation and Hippo signalling pathway during liver regeneration (PH) is still unclear. In this study, we investigated the regulatory mechanism of LATS1, a pivotal protein in the Hippo signalling pathway, on liver regeneration and explored the specific mechanism of DNA methylation regulating LATS1. To analyse the regulation of LATS1 by DNA methylation, following 2/3 partial hepatectomy (PH) in liver-specific AAV-8 shDNMT3B deleted mice (DNMT3B, KD) mice and sex-matched AAV-8 shControl (Control). We determined that DNMT3B regulates the protein expression of LATS1 by DNA methylation. miR-29b-3p significantly regulates the expression of DNMT3B and alters LATS1 expression to inactivate the Hippo signalling pathway, thereby reducing the expression of cell proliferation and cycle proteins and inhibiting liver regeneration. Our results indicated that the miR-29b-3p/DNMT3B regulatory axis influences LATS1 expression through DNA methylation, and thereby promotes liver regeneration.
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Affiliation(s)
- Yinwen Zhou
- Department of Hepatobiliary Surgery and Organ TransplantationGuizhou Provincial People's HospitalGuiyangGuizhouChina
- Department of Hepatobiliary SurgeryZunyi Medical UniversityZunyiGuizhouChina
| | - Hao Wu
- Division of Breast Surgery, Department of General Surgery, Breast Center, West China HospitalSichuan UniversityChengduSichuanChina
| | - Qiu Wang
- Department of Hepatobiliary Surgery and Organ TransplantationGuizhou Provincial People's HospitalGuiyangGuizhouChina
| | - Bo Ma
- Department of Hepatobiliary Surgery and Organ TransplantationGuizhou Provincial People's HospitalGuiyangGuizhouChina
| | - Jiulong Sun
- Department of Hepatobiliary Surgery and Organ TransplantationGuizhou Provincial People's HospitalGuiyangGuizhouChina
- Department of Hepatobiliary SurgeryZunyi Medical UniversityZunyiGuizhouChina
| | - Guoliang Wang
- Department of Hepatobiliary Surgery and Organ TransplantationGuizhou Provincial People's HospitalGuiyangGuizhouChina
- Department of Hepatobiliary SurgeryZunyi Medical UniversityZunyiGuizhouChina
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37
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Ajongbolo AO, Langhans SA. YAP/TAZ-associated cell signaling - at the crossroads of cancer and neurodevelopmental disorders. Front Cell Dev Biol 2025; 13:1522705. [PMID: 39936032 PMCID: PMC11810912 DOI: 10.3389/fcell.2025.1522705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025] Open
Abstract
YAP/TAZ (Yes-associated protein/paralog transcriptional co-activator with PDZ-binding domain) are transcriptional cofactors that are the key and major downstream effectors of the Hippo signaling pathway. Both are known to play a crucial role in defining cellular outcomes, including cell differentiation, cell proliferation, and apoptosis. Aside from the canonical Hippo signaling cascade with the key components MST1/2 (mammalian STE20-like kinase 1/2), SAV1 (Salvador homologue 1), MOB1A/B (Mps one binder kinase activator 1A/B) and LATS1/2 (large tumor suppressor kinase 1/2) upstream of YAP/TAZ, YAP/TAZ activation is also influenced by numerous other signaling pathways. Such non-canonical regulation of YAP/TAZ includes well-known growth factor signaling pathways such as the epidermal growth factor receptor (EGFR)/ErbB family, Notch, and Wnt signaling as well as cell-cell adhesion, cell-matrix interactions and mechanical cues from a cell's microenvironment. This puts YAP/TAZ at the center of a complex signaling network capable of regulating developmental processes and tissue regeneration. On the other hand, dysregulation of YAP/TAZ signaling has been implicated in numerous diseases including various cancers and neurodevelopmental disorders. Indeed, in recent years, parallels between cancer development and neurodevelopmental disorders have become apparent with YAP/TAZ signaling being one of these pathways. This review discusses the role of YAP/TAZ in brain development, cancer and neurodevelopmental disorders with a special focus on the interconnection in the role of YAP/TAZ in these different conditions.
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Affiliation(s)
- Aderonke O. Ajongbolo
- Division of Neurology and Nemours Biomedical Research, Nemours Children’s Health, Wilmington, DE, United States
- Biological Sciences Graduate Program, University of Delaware, Newark, DE, United States
| | - Sigrid A. Langhans
- Division of Neurology and Nemours Biomedical Research, Nemours Children’s Health, Wilmington, DE, United States
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Garcia KC, Khan AA, Ghosh K, Sinha S, Scalora N, DeWane G, Fullenkamp C, Merritt N, Drebot Y, Yu S, Leidinger M, Henry MD, Breheny P, Chimenti MS, Tanas MR. PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.21.634138. [PMID: 39896636 PMCID: PMC11785051 DOI: 10.1101/2025.01.21.634138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Purpose Sarcomas are a heterogeneous group of cancers with few shared therapeutic targets. PI3K signaling is activated in various subsets of sarcomas, representing a shared oncogenic signaling pathway. Oncogenic PI3K signaling has been challenging to target therapeutically. An integrated view of PI3K and Hippo pathway signaling is examined to determine if this could be leveraged therapeutically. Experimental design A tissue microarray containing sarcomas of various histological types was evaluated for PTEN loss and correlated with levels of activated TAZ and YAP. PI3K and Hippo pathways were dissected in sarcoma cell lines. The role of TAZ and YAP were evaluated in a PI3K-driven mouse model. The efficacy of mTORC1 inhibition and TEAD inhibition were evaluated in sarcoma cell lines and in vivo . Results PI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30-60%), representing a common therapeutic target. TAZ and YAP are transcriptional co-activators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage independent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effect in vivo , reducing tumor proliferation and size. Conclusions TAZ and YAP are transcriptional co-activators downstream of PI3K signaling, a pathway that has lacked a well-defined oncogenic transcription factor. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis allowing for synergistic combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1 in sarcomas.
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39
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Wu SS, Zhao XY, Yang L, Hai C, Wu D, Liu XF, Song LS, Bai CL, Su GH, Li GP. Transcription coactivator YAP1 promotes CCND1/CDK6 expression, stimulating cell proliferation in cloned cattle placentas. Zool Res 2025; 46:122-138. [PMID: 39846191 PMCID: PMC11890997 DOI: 10.24272/j.issn.2095-8137.2024.211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 10/22/2024] [Indexed: 01/24/2025] Open
Abstract
Somatic cell nuclear transfer (SCNT) has been successfully employed across various mammalian species, yet cloned animals consistently exhibit low pregnancy rates, primarily due to placental abnormalities such as hyperplasia and hypertrophy. This study investigated the involvement of the Hippo signaling pathway in aberrant placental development in SCNT-induced bovine pregnancies. SCNT-derived cattle exhibited placental hypertrophy, including enlarged abdominal circumference and altered placental cotyledon morphology. RNA sequencing analysis indicated significant dysregulation of Hippo signaling pathway genes in SCNT placentas. Co-expression of YAP1 and CCND1 was observed in cloned blastocysts, placental tissues, and bovine placental mesenchymal stem cells (bPMSCs). Manipulation of YAP1 expression demonstrated the capacity to regulate bPMSC proliferation. Experimental assays confirmed the direct binding of YAP1 to CCND1, which subsequently promoted CCND1 expression in bPMSCs. Furthermore, inhibition of CDK6, a downstream target of CCND1, attenuated SCNT bPMSC proliferation. This study identified YAP1 as a key regulatory component within the Hippo signaling pathway that drives placental hyperplasia in cloned cattle through up-regulation of CCND1-CDK6 expression, facilitating cell cycle progression. These findings offer potential avenues for enhancing cloning efficiency, with implications for evolutionary biology and the conservation of valuable germplasm resources.
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Affiliation(s)
- Shan-Shan Wu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
| | - Xiao-Yu Zhao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
| | - Lei Yang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
| | - Chao Hai
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
| | - Di Wu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
| | - Xue-Fei Liu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
| | - Li-Shuang Song
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
| | - Chun-Ling Bai
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
| | - Guang-Hua Su
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China. E-mail:
| | - Guang-Peng Li
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
- College of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China. E-mail:
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Jiang D, Li P, Lu Y, Tao J, Hao X, Wang X, Wu W, Xu J, Zhang H, Li X, Chen Y, Jin Y, Zhang L. A feedback loop between Paxillin and Yorkie sustains Drosophila intestinal homeostasis and regeneration. Nat Commun 2025; 16:570. [PMID: 39794306 PMCID: PMC11724037 DOI: 10.1038/s41467-024-55255-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 12/04/2024] [Indexed: 01/13/2025] Open
Abstract
Balanced self-renewal and differentiation of stem cells are crucial for maintaining tissue homeostasis, but the underlying mechanisms of this process remain poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Pax, which is orthologous to mammalian PXN, coordinates the proliferation and differentiation of ISCs during both normal homeostasis and injury-induced midgut regeneration in Drosophila. Loss of Pax promotes ISC proliferation while suppressing its differentiation into absorptive enterocytes (ECs). Mechanistically, our findings demonstrate that Pax is a conserved target gene of the Hippo signaling pathway in both Drosophila and mammals. Subsequent investigations have revealed Pax interacts with Yki and enhances its cytoplasmic localization, thereby establishing a feedback regulatory mechanism that attenuates Yki activity and ultimately inhibits ISCs proliferation. Additionally, Pax induces the differentiation of ISCs into ECs by activating Notch expression, thus facilitating the differentiation process. Overall, our study highlights Pax as a pivotal component of the Hippo and Notch pathways in regulating midgut homeostasis, shedding light on this growth-related pathway in tissue maintenance and intestinal function.
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Affiliation(s)
- Dan Jiang
- The Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200233, China
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minghang, Shanghai, 200240, China
| | - Pengyue Li
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yi Lu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jiaxin Tao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xue Hao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xiaodong Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Wei Wu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jinjin Xu
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minghang, Shanghai, 200240, China
| | - Haoen Zhang
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xiaoyu Li
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yixing Chen
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yunyun Jin
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minghang, Shanghai, 200240, China.
| | - Lei Zhang
- The Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200233, China.
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minghang, Shanghai, 200240, China.
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
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Jeon S, Jeon Y, Lim JY, Kim Y, Cha B, Kim W. Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets. Signal Transduct Target Ther 2025; 10:4. [PMID: 39757214 DOI: 10.1038/s41392-024-02070-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/01/2024] [Accepted: 11/06/2024] [Indexed: 01/07/2025] Open
Abstract
Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed through the condensation of proteins, nucleic acids, and other molecules-in driving efficient and dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression and intracellular signal transduction, enabling rapid and finely tuned cellular responses. Their ability to regulate cellular signaling pathways is particularly significant, as it requires a careful balance between flexibility and precision. Disruption of this balance can lead to pathological conditions, including neurodegenerative diseases, cancer, and viral infections. Consequently, biomolecular condensates have emerged as promising therapeutic targets, with the potential to offer novel approaches to disease treatment. In this review, we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways, their roles in health and disease, and potential strategies for modulating condensate dynamics as a therapeutic approach. Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.
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Affiliation(s)
- Soyoung Jeon
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Yeram Jeon
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Ji-Youn Lim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea
| | - Yujeong Kim
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Boksik Cha
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea.
| | - Wantae Kim
- Department of Life Science, University of Seoul, Seoul, South Korea.
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42
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Li Y, Du J, Deng S, Liu B, Jing X, Yan Y, Liu Y, Wang J, Zhou X, She Q. The molecular mechanisms of cardiac development and related diseases. Signal Transduct Target Ther 2024; 9:368. [PMID: 39715759 DOI: 10.1038/s41392-024-02069-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/28/2024] [Accepted: 11/04/2024] [Indexed: 12/25/2024] Open
Abstract
Cardiac development is a complex and intricate process involving numerous molecular signals and pathways. Researchers have explored cardiac development through a long journey, starting with early studies observing morphological changes and progressing to the exploration of molecular mechanisms using various molecular biology methods. Currently, advancements in stem cell technology and sequencing technology, such as the generation of human pluripotent stem cells and cardiac organoids, multi-omics sequencing, and artificial intelligence (AI) technology, have enabled researchers to understand the molecular mechanisms of cardiac development better. Many molecular signals regulate cardiac development, including various growth and transcription factors and signaling pathways, such as WNT signaling, retinoic acid signaling, and Notch signaling pathways. In addition, cilia, the extracellular matrix, epigenetic modifications, and hypoxia conditions also play important roles in cardiac development. These factors play crucial roles at one or even multiple stages of cardiac development. Recent studies have also identified roles for autophagy, metabolic transition, and macrophages in cardiac development. Deficiencies or abnormal expression of these factors can lead to various types of cardiac development abnormalities. Nowadays, congenital heart disease (CHD) management requires lifelong care, primarily involving surgical and pharmacological treatments. Advances in surgical techniques and the development of clinical genetic testing have enabled earlier diagnosis and treatment of CHD. However, these technologies still have significant limitations. The development of new technologies, such as sequencing and AI technologies, will help us better understand the molecular mechanisms of cardiac development and promote earlier prevention and treatment of CHD in the future.
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Affiliation(s)
- Yingrui Li
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianlin Du
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Songbai Deng
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bin Liu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaodong Jing
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuling Yan
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yajie Liu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Wang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaobo Zhou
- Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany; DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany
| | - Qiang She
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Xu K, Zhu S, Xu F, Yang J, Deng B, Su D, Ma J, Zu M, Lin Y, Pei T, Zhu Y, Wang L, Liu D, Duan Q, Xu J, Pan Z, Tao J, Hou Z. Toxoplasma gondii induces MST2 phosphorylation mediating the activation of hippo signaling pathway to promote apoptosis and lung tissue damage. iScience 2024; 27:111312. [PMID: 39640582 PMCID: PMC11618000 DOI: 10.1016/j.isci.2024.111312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 09/23/2024] [Accepted: 10/30/2024] [Indexed: 12/07/2024] Open
Abstract
Toxoplasma gondii (T. gondii) is an intracellular parasite, and its regulation of host cell apoptosis directly affects its parasitism. Studies link T. gondii-induced apoptosis to abnormal expression of mammalian STE20-like protein kinase 2 (MST2), but its precise role remains unclear. In this study, the regulatory roles in apoptosis and pathogenicity of T. gondii infection were identified in vitro and in vivo. Simultaneously, MST2 and Hippo signaling pathway activation induced by T. gondii were evaluated. MST2 overexpression and knockout were used to assess its regulatory role in apoptosis and Hippo signaling pathway. Results showed that T. gondii induced apoptosis and lung damage, with Hippo signaling pathway activation via MST2 phosphorylation. MST2 was demonstrated to regulate apoptosis and Hippo signaling pathway. Notably, MST2 knockout hindered the T. gondii-induced apoptosis and weakened Hippo signaling pathway activation. MST2 is an important target for T. gondii to control host cell fate and modulate immune responses.
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Affiliation(s)
- Kangzhi Xu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Shifan Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Fan Xu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Jin Yang
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225000, China
| | - Bin Deng
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou 225000, China
| | - Dingzeyang Su
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Jing Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Mingyue Zu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Yifan Lin
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Tianxu Pei
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Yuyang Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Lele Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Dandan Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Qiangde Duan
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Jinjun Xu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Zhiming Pan
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Jianping Tao
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
| | - Zhaofeng Hou
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou 225009, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou 225009, China
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Zhu R, Jiao Z, Yu FX. Advances towards potential cancer therapeutics targeting Hippo signaling. Biochem Soc Trans 2024; 52:2399-2413. [PMID: 39641583 DOI: 10.1042/bst20240244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/06/2024] [Accepted: 11/06/2024] [Indexed: 12/07/2024]
Abstract
Decades of research into the Hippo signaling pathway have greatly advanced our understanding of its roles in organ growth, tissue regeneration, and tumorigenesis. The Hippo pathway is frequently dysregulated in human cancers and is recognized as a prominent cancer signaling pathway. Hence, the Hippo pathway represents an ideal molecular target for cancer therapies. This review will highlight recent advancements in targeting the Hippo pathway for cancer treatment and discuss the potential opportunities for developing new therapeutic modalities.
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Affiliation(s)
- Rui Zhu
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhihan Jiao
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Fa-Xing Yu
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Li Y, Liu D, Zhang S, Zhou J, Li S. Outstretched wing is controlled by intestinal enteroblasts-derived unpaired 2 cytokine signaling in Drosophila. FASEB J 2024; 38:e70227. [PMID: 39636270 DOI: 10.1096/fj.202402392r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/12/2024] [Accepted: 11/21/2024] [Indexed: 12/07/2024]
Abstract
The outstretched wing phenotype in Drosophila melanogaster can be induced by various genetic mutations and environmental perturbations, yet the role of gut-derived signals in coordinating wing development remains largely unexplored. In this study, we demonstrate that Upd2, secreted from the gut to the wing discs, plays a crucial role in regulating the outstretched wing phenotype. The intestinal precursor cell driver esg-Gal4 exhibits low levels of leaky expression, even in the presence of Gal80ts at room temperature (25°C). This leaky expression of TDP-43, Notch, and Yki in intestinal precursor cells leads to a held-out wing phenotype, shortened lifespan, and impaired locomotor function. Although esg-Gal4 is expressed in imaginal discs, overexpression of TDP-43, Notch, or Yki using the wing-specific driver does not result in the outstretched wing. Furthermore, our data indicate that genetic alterations associated with the spread-out wing phenotype originate in enteroblasts (EBs) during early development. RNA sequencing analysis with guts from third instar larvae revealed that the JAK-STAT pathway ligand Upd2 is among the most significantly downregulated transcripts. Notably, ectopic expression of Upd2 in EBs partially rescued the abnormal held-out wing phenotype induced by TDP-43, Notch, and Yki overexpression. Together, our findings identify gut-derived Upd2 cytokine signaling as a key mediator of the outstretched wing phenotype, providing evidence for gut-to-wing communication axis during Drosophila development.
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Affiliation(s)
- Yu Li
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Dongyue Liu
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Shengliang Zhang
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Jinglan Zhou
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Shuangxi Li
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
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Wang L, Zeng T, Wang Y, Wang G, Yu W, Zhang J, Shi Y, Li J, Ding J. K90 lactylation orchestrates YAP nuclear sequestration by impairing binding with exportin CRM1 and enhances HCC malignancy. Cancer Lett 2024; 611:217386. [PMID: 39645025 DOI: 10.1016/j.canlet.2024.217386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 09/13/2024] [Accepted: 12/04/2024] [Indexed: 12/09/2024]
Affiliation(s)
- Li Wang
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China.
| | - Tanlun Zeng
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China
| | - Yichuan Wang
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China
| | - Guang Wang
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China
| | - Weichen Yu
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China
| | - Jian Zhang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Yihai Shi
- Department of Gastroenterology, Shanghai Pudong New Area Gongli Hospital, Shanghai, 200135, China
| | - Jixi Li
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Huashan Hospital, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, 200438, China
| | - Jin Ding
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China.
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Kot A, Koszewska D, Ochman B, Świętochowska E. Clinical Potential of Misshapen/NIKs-Related Kinase (MINK) 1-A Many-Sided Element of Cell Physiology and Pathology. Curr Issues Mol Biol 2024; 46:13811-13845. [PMID: 39727954 PMCID: PMC11727420 DOI: 10.3390/cimb46120826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/29/2024] [Accepted: 12/03/2024] [Indexed: 12/28/2024] Open
Abstract
Misshapen/NIKs-related kinase (MINK) 1 belongs to the mammalian germinal center kinase (GCK) family. It contains the N-terminal, conserved kinase domain, a coiled-coil region, a proline-rich region, and a GCK, C-terminal domain with the Citron-NIK-Homology (CNH) domain. The kinase is an essential component of cellular signaling pathways, which include Wnt signaling, JNK signaling, pathways engaging Ras proteins, the Hippo pathway, and STRIPAK complexes. It thus contributes to regulating the cell cycle, apoptosis, cytoskeleton organization, cell migration, embryogenesis, or tissue homeostasis. MINK1 plays an important role in immunological responses, inhibiting Th17 and Th1 cell differentiation and regulating NLRP3 inflammasome function. It may be considered a link between ROS and the immunological system, and a potential antiviral target for human enteroviruses. The kinase has been implicated in the pathogenesis of sepsis, rheumatoid arthritis, asthma, SLE, and more. It is also involved in tumorigenesis and drug resistance in cancer. Silencing MINK1 reduces cancer cell migration, suggesting potential for new therapeutic approaches. Targeting MINK1 could be a promising treatment strategy for patients insensitive to current chemotherapies, and could improve their prognosis. Moreover, MINK1 plays an important role in the nervous system and the cardiovascular system development and function. The modulation of MINK1 activity could influence the course of neurodegenerative diseases, including Alzheimer's disease. Further exploration of the activity of the kinase could also help in gaining more insight into factors involved in thrombosis or congenital heart disease. This review aims to summarize the current knowledge on MINK1, highlight its therapeutic and prognostic potential, and encourage more studies in this area.
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Affiliation(s)
| | | | | | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland; (A.K.); (D.K.); (B.O.)
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Ouarné M, Pena A, Ramalho D, Conchinha NV, Costa T, Enjalbert R, Figueiredo AM, Saraiva MP, Carvalho Y, Bernabeu MO, Henao Misikova L, Oh SP, Franco CA. A non-genetic model of vascular shunts informs on the cellular mechanisms of formation and resolution of arteriovenous malformations. Cardiovasc Res 2024; 120:1967-1984. [PMID: 39308243 PMCID: PMC11629978 DOI: 10.1093/cvr/cvae160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 04/11/2024] [Accepted: 05/23/2024] [Indexed: 12/11/2024] Open
Abstract
AIMS Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to AV shunt formation and how shunts can be reverted are poorly understood. METHODS AND RESULTS Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in the volume of venous endothelial cells (EC)-hypertrophic venous cells-are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of the mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signalling cell-autonomously regulates EC volume in pro-angiogenic conditions, establishing a link with hereditary haemorrhagic telangiectasia-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts. CONCLUSION Our findings highlight that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocate for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs.
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Affiliation(s)
- Marie Ouarné
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
| | - Andreia Pena
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
- Católica Biomedical Research Centre, Universidade Católica Portuguesa, Católica Medical School, Lisbon 1649-023, Portugal
| | - Daniela Ramalho
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
- Católica Biomedical Research Centre, Universidade Católica Portuguesa, Católica Medical School, Lisbon 1649-023, Portugal
| | - Nadine V Conchinha
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
| | - Tiago Costa
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
| | - Romain Enjalbert
- Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh EH16 4UX, UK
| | - Ana M Figueiredo
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
| | - Marta Pimentel Saraiva
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
| | - Yulia Carvalho
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
| | - Miguel O Bernabeu
- Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh EH16 4UX, UK
- The Bayes Centre, The University of Edinburgh, Edinburgh EH8 9BT, UK
| | - Lenka Henao Misikova
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
- Católica Biomedical Research Centre, Universidade Católica Portuguesa, Católica Medical School, Lisbon 1649-023, Portugal
| | - S Paul Oh
- Barrow Aneurysm & AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | - Cláudio A Franco
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal
- Católica Biomedical Research Centre, Universidade Católica Portuguesa, Católica Medical School, Lisbon 1649-023, Portugal
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Abedimanesh S, Safaralizadeh R, Jahanafrooz Z, Najafi S, Amini M, Nazarloo SS, Bahojb Mahdavi SZ, Baradaran B, Jebelli A, Mokhtarzadeh AA. Interaction of noncoding RNAs with hippo signaling pathway in cancer cells and cancer stem cells. Noncoding RNA Res 2024; 9:1292-1307. [PMID: 39045083 PMCID: PMC11263728 DOI: 10.1016/j.ncrna.2024.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 06/02/2024] [Accepted: 06/05/2024] [Indexed: 07/25/2024] Open
Abstract
The Hippo signaling pathway has a regulatory function in the organogenesis process and cellular homeostasis, switching the cascade reactions of crucial kinases acts to turn off/on the Hippo pathway, altering the downstream gene expression and thereby regulating proliferation, apoptosis, or stemness. Disruption of this pathway can lead to the occurrence of various disorders and different types of cancer. Recent findings highlight the importance of ncRNAs, such as microRNA, circular RNA, and lncRNAs, in modulating the Hippo pathway. Defects in ncRNAs can disrupt Hippo pathway balance, increasing tumor cells, tumorigenesis, and chemotherapeutic resistance. This review summarizes ncRNAs' inhibitory or stimulatory role in - Hippo pathway regulation in cancer and stem cells. Identifying the relation between ncRNAs and the components of this pathway could pave the way for developing new biomarkers in the treatment and diagnosis of cancers.
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Affiliation(s)
- Saba Abedimanesh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Zohreh Jahanafrooz
- Department of Biology, Faculty of Sciences, University of Maragheh, Maragheh, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shabnam Soltani Nazarloo
- Department of Biology, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asiyeh Jebelli
- Department of Biological Sciences, Faculty of Basic Sciences, Higher Education Institute of Rab-Rashid, Tabriz, Iran
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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50
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Lukose G, Al Assaad M, Driskill JH, Levine MF, Gundem G, Semaan A, Wilkes DC, Spigland NA, Medina-Martínez JS, Sboner A, Elemento O, Jessurun J, Mosquera JM. Whole genome profiling of rare pediatric thoracic tumors elucidates a YAP1::LEUTX fusion in an unclassified biphasic embryonal neoplasm. Pathol Res Pract 2024; 264:155726. [PMID: 39566337 DOI: 10.1016/j.prp.2024.155726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 11/13/2024] [Indexed: 11/22/2024]
Abstract
Malignant biphasic tumors of the lungs are rare, more so in the pediatric population. Here, we present the whole-genome characterization of a pleuropulmonary blastoma Type III and an unclassified biphasic thoracic embryonal neoplasm. The pleuropulmonary blastoma harbored pathogenic DICER1 germline and somatic mutations, and additional somatic variants in TP53 and BCOR. The other malignant tumor demonstrated a t(11;19) balanced translocation with a YAP1::LEUTX fusion that was confirmed by fluorescence in situ hybridization. No DICER1 germline or somatic mutation was present. YAP1 and LEUTX have been implicated in tumorigenesis of various neoplasms, and YAP1 fusion genes are an emerging oncogenic entity in a variety of malignancies. In this study we highlight the importance of whole-genome characterization of rare and unclassified tumors to identify biologic mechanisms and potential therapeutic targets.
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Affiliation(s)
- Georgi Lukose
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Majd Al Assaad
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Jordan H Driskill
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | | | | | - Alissa Semaan
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA
| | - David C Wilkes
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Nitsana A Spigland
- Department of Surgery, Division of Pediatric Surgery, Weill Cornell Medicine / NewYork-Presbyterian Hospital, New York, NY, USA
| | | | - Andrea Sboner
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Olivier Elemento
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA
| | - José Jessurun
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Juan Miguel Mosquera
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
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