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Takikawa M, Nakano A, Krishnaraj J, Tabata Y, Watanabe Y, Okabe A, Sakaguchi Y, Fujiki R, Mochizuki A, Tajima T, Sada A, Matsushita S, Wakabayashi Y, Araki K, Kaneda A, Ishikawa F, Sadaie M, Ohki R. Extrinsic induction of apoptosis and tumor suppression via the p53-Reprimo-Hippo-YAP/TAZ-p73 pathway. Proc Natl Acad Sci U S A 2025; 122:e2413126122. [PMID: 39913207 PMCID: PMC11831151 DOI: 10.1073/pnas.2413126122] [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: 07/01/2024] [Accepted: 01/03/2025] [Indexed: 02/19/2025] Open
Abstract
Tumor progression is suppressed by inherent cellular mechanisms such as apoptosis. The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and plays a pivotal role in tumor suppression. RPRM is a target gene of p53 known to be involved in tumor suppression, but its molecular function has remained elusive. Here, we report that Reprimo (the protein product of RPRM) is secreted and extrinsically induces apoptosis in recipient cells. We identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as receptors for Reprimo. Subsequent analyses revealed that Reprimo acts upstream of the Hippo-YAP/TAZ-p73 axis and induces apoptosis by transactivating various proapoptotic genes. In vivo analyses further support the tumor-suppressive effects of secreted Reprimo. These findings identify the p53-Reprimo-Hippo-YAP/TAZ-p73 axis as an extrinsic apoptosis pathway that plays a crucial role in tumor suppression. Our finding of the innate tumor eliminator Reprimo and the downstream pathway offers a promising avenue for the pharmacological treatment of cancer.
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Affiliation(s)
- Masahiro Takikawa
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba278-8510, Japan
| | - Airi Nakano
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
- Department of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki852-8523, Japan
| | - Jayaraman Krishnaraj
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
| | - Yuko Tabata
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
| | - Yuzo Watanabe
- Proteomics Facility, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto606-8502, Japan
| | - Atsushi Okabe
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chuo‐ku, Chiba260‐8670, Japan
- Health and Disease Omics Center, Chiba University, Chuo‐ku, Chiba260‐8670, Japan
| | - Yukiko Sakaguchi
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
| | - Ryoji Fujiki
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chuo‐ku, Chiba260‐8670, Japan
| | - Ami Mochizuki
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
| | - Tomoko Tajima
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
| | - Akane Sada
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
| | - Shu Matsushita
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
| | - Yuichi Wakabayashi
- Cancer Genome Center, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, Chuo-ku, Chiba260-8717, Japan
| | - Kimi Araki
- Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Chuo-ku, Kumamoto860-0811, Japan
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Honjo, Kumamoto860-8556, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chuo‐ku, Chiba260‐8670, Japan
- Health and Disease Omics Center, Chiba University, Chuo‐ku, Chiba260‐8670, Japan
| | - Fuyuki Ishikawa
- Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto606-8501, Japan
| | - Mahito Sadaie
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba278-8510, Japan
| | - Rieko Ohki
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Chuo-ku, Tokyo104-0045, Japan
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2
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Pankratova MD, Riabinin AA, Butova EA, Selivanovskiy AV, Morgun EI, Ulianov SV, Vorotelyak EA, Kalabusheva EP. YAP/TAZ Signalling Controls Epidermal Keratinocyte Fate. Int J Mol Sci 2024; 25:12903. [PMID: 39684613 DOI: 10.3390/ijms252312903] [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: 11/05/2024] [Revised: 11/24/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
The paralogues Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) control cell proliferation and cell fate determination from embryogenesis to ageing. In the skin epidermis, these proteins are involved in both homeostatic cell renewal and injury-induced regeneration and also drive carcinogenesis and other pathologies. YAP and TAZ are usually considered downstream of the Hippo pathway. However, they are the central integrating link for the signalling microenvironment since they are involved in the interplay with signalling cascades induced by growth factors, cytokines, and physical parameters of the extracellular matrix. In this review, we summarise the evidence on how YAP and TAZ are activated in epidermal keratinocytes; how YAP/TAZ-mediated signalling cooperates with other signalling molecules at the plasma membrane, cytoplasmic, and nuclear levels; and how YAP/TAZ ultimately controls transcription programmes, defining epidermal cell fate.
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Affiliation(s)
- Maria D Pankratova
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Andrei A Riabinin
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Elizaveta A Butova
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Arseniy V Selivanovskiy
- Laboratory of Structural-Functional Organization of Chromosomes, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
- Department of Molecular Biology, Faculty of Biology, M.V. Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Elena I Morgun
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Sergey V Ulianov
- Laboratory of Structural-Functional Organization of Chromosomes, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
- Department of Molecular Biology, Faculty of Biology, M.V. Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Ekaterina A Vorotelyak
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Ekaterina P Kalabusheva
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
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3
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Shahpari M, Hashemi M, Younesirad T, Hasanzadeh A, Mosanne MM, Ahmadifard M. The functional roles of competitive endogenous RNA (ceRNA) networks in apoptosis in human cancers: The circRNA/miRNA/mRNA regulatory axis and cell signaling pathways. Heliyon 2024; 10:e37089. [PMID: 39524849 PMCID: PMC11546195 DOI: 10.1016/j.heliyon.2024.e37089] [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: 08/18/2024] [Accepted: 08/27/2024] [Indexed: 11/16/2024] Open
Abstract
Circular RNAs are noncoding RNAs with circular conformation mainly due to backsplicing event. CircRNAs can potentially impact cell biological processes by interacting with cell signaling pathways. Numerous circRNAs have been found to be aberrantly expressed in a variety of cancers. These RNAs can act as ceRNA (competitive endogenous RNA) by sponging certain miRNAs to form circRNA/miRNA/mRNA networks. Dysregulation of ceRNA networks may lead to dysfunctions in various cell pathways, which modulate apoptosis-associated genes and ultimately result in cancer progression. Since disruption of apoptosis is one of the leading causes of cancer development, one approach for cancer treatment is to drive cells toward apoptosis. In this review, we present a summary of studies on the role of ceRNA networks in cellular signaling pathways that regulate apoptosis; these networks are suggested to be potential biomarkers for cancer treatment.
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Affiliation(s)
| | | | - Tayebeh Younesirad
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Aida Hasanzadeh
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad mahdi Mosanne
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohamadreza Ahmadifard
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
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4
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Sharma R, Sharma S, Shriwas P, Mehta L, Vu AH, Mouw JK, Koo J, Huang C, Matsuk VY, Tucker-Burden C, Joseph G, Behera M, Sun SY, Roy MA, Gilbert-Ross M, Leal T, Marcus AI, Shanmugam M. Intra-tumoral YAP and TAZ heterogeneity drives collective NSCLC invasion that is targeted by SUMOylation inhibitor TAK-981. iScience 2024; 27:111133. [PMID: 39524367 PMCID: PMC11544388 DOI: 10.1016/j.isci.2024.111133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/15/2024] [Accepted: 10/07/2024] [Indexed: 11/16/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) collective invasion is supported by cooperativity of proliferative (follower) and invasive (leader) cells. H1299-isolated follower cells exhibit higher Yes-associated protein (YAP) expression, while leader cells were found to express elevated transcriptional coactivator with PDZ-binding motif (TAZ/WWTR1) expression. Suppressing TAZ (not YAP) in leader cells reduced invasion. TAZ-regulated leader cell invasion is associated with activation of the EGFR-PI3K-AKT axis. NSCLC patient samples also demonstrated heterogeneity in YAP and TAZ expression. YAP and TAZ regulate proliferation of follower and leader cells. Our results highlight the need to inhibit both YAP and TAZ to effectively target their regulation of collective invasion. We identify that the SUMOylation inhibitor TAK-981 reduces YAP and TAZ expression, decreasing tumor burden and metastasis in a murine NSCLC model. Our study reveals an intra-tumoral division of labor, driven by differential YAP and TAZ expression, which can be effectively targeted with TAK-981 for NSCLC therapy.
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Affiliation(s)
- Richa Sharma
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Shagun Sharma
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Pratik Shriwas
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Labdhi Mehta
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - An H. Vu
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Janna K. Mouw
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Junghui Koo
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Chunzi Huang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Veronika Y. Matsuk
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Carol Tucker-Burden
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Gregory Joseph
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Madhusmita Behera
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Shi-Yong Sun
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Melissa A. Roy
- Division of Pathology, Emory National Primate Research Center, Atlanta, GA, USA
| | - Melissa Gilbert-Ross
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Ticiana Leal
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Adam I. Marcus
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
| | - Mala Shanmugam
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA
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5
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Chen X, Li D, Su Q, Ling X, Yang Y, Liu Y, Zhu X, He A, Ding S, Xu R, Liu Z, Long X, Zhang J, Yang Z, Qi Y, Wu H. SENP3 mediates the deSUMOylation and degradation of YAP1 to regulate the progression of triple-negative breast cancer. J Biol Chem 2024; 300:107764. [PMID: 39270822 PMCID: PMC11490879 DOI: 10.1016/j.jbc.2024.107764] [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: 03/17/2024] [Revised: 07/23/2024] [Accepted: 08/15/2024] [Indexed: 09/15/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is a prevalent malignancy in women, casting a formidable shadow on their well-being. Positioned within the nucleolus, SUMO-specific protease 3 (SENP3) assumes a pivotal role in the realms of development and tumorigenesis. However, the participation of SENP3 in TNBC remains a mystery. Here, we elucidate that SENP3 exerts inhibitory effects on migration and invasion capacities, as well as on the stem cell-like phenotype, within TNBC cells. Further experiments showed that YAP1 is the downstream target of SENP3, and SENP3 regulates tumorigenesis in a YAP1-dependent manner. YAP1 is found to be SUMOylated and SENP3 deconjugates SUMOylated YAP1 and promotes degradation mediated by the ubiquitin-proteasome system. More importantly, YAP1 with a mutation at the SUMOylation site impedes the capacity of WT YAP1 in TNBC tumorigenesis. Taken together, our findings firmly establish the pivotal role of SENP3 in the modulation of YAP1 deSUMOylation, unveiling novel mechanistic insight into the important role of SENP3 in the regulation of TNBC tumorigenesis in a YAP1-dependent manner.
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Affiliation(s)
- Xu Chen
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Danqing Li
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Qi Su
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Xing Ling
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Yanyan Yang
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Yuhang Liu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Xinjie Zhu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Anqi He
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Siyu Ding
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Runxiao Xu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Zhaoxia Liu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Xiaojun Long
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Jinping Zhang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Zhihui Yang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yitao Qi
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China.
| | - Hongmei Wu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China.
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6
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Hikasa H, Kawahara K, Inui M, Yasuki Y, Yamashita K, Otsubo K, Kitajima S, Nishio M, Arima K, Endo M, Taira M, Suzuki A. A highly sensitive reporter system to monitor endogenous YAP1/TAZ activity and its application in various human cells. Cancer Sci 2024; 115:3370-3383. [PMID: 39155534 PMCID: PMC11447953 DOI: 10.1111/cas.16316] [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: 03/25/2024] [Revised: 07/22/2024] [Accepted: 08/01/2024] [Indexed: 08/20/2024] Open
Abstract
The activation of yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) has been implicated in both regeneration and tumorigenesis, thus representing a double-edged sword in tissue homeostasis. However, how the activity of YAP1/TAZ is regulated or what leads to its dysregulation in these processes remains unknown. To explore the upstream stimuli modulating the cellular activity of YAP1/TAZ, we developed a highly sensitive YAP1/TAZ/TEAD-responsive DNA element (YRE) and incorporated it into a lentivirus-based reporter cell system to allow for sensitive and specific monitoring of the endogenous activity of YAP1/TAZ in terms of luciferase activity in vitro and Venus fluorescence in vivo. Furthermore, by replacing YRE with TCF- and NF-κB-binding DNA elements, we demonstrated the applicability of this reporter system to other pathways such as Wnt/β-catenin/TCF- and IL-1β/NF-κB-mediated signaling, respectively. The practicality of this system was evaluated by performing cell-based reporter screening of a chemical compound library consisting of 364 known inhibitors, using reporter-introduced cells capable of quantifying YAP1/TAZ- and β-catenin-mediated transcription activities, which led to the identification of multiple inhibitors, including previously known as well as novel modulators of these signaling pathways. We further confirmed that novel YAP1/TAZ modulators, such as potassium ionophores, Janus kinase inhibitors, platelet-derived growth factor receptor inhibitors, and genotoxic stress inducers, alter the protein level or phosphorylation of endogenous YAP1/TAZ and the expression of their target genes. Thus, this reporter system provides a powerful tool to monitor endogenous signaling activities of interest (even in living cells) and search for modulators in various cellular contexts.
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Affiliation(s)
- Hiroki Hikasa
- Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
- Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Kohichi Kawahara
- Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masako Inui
- Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Yukichika Yasuki
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Department of Chemistry and Bioscience, Graduate School of Science and Engineering, Kagoshima University, Kagoshima, Japan
| | - Keita Yamashita
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Department of Chemistry and Bioscience, Graduate School of Science and Engineering, Kagoshima University, Kagoshima, Japan
| | - Kohei Otsubo
- Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shojiro Kitajima
- Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Miki Nishio
- Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazunari Arima
- Department of Chemistry and Bioscience, Graduate School of Science and Engineering, Kagoshima University, Kagoshima, Japan
| | - Motoyoshi Endo
- Department of Molecular Biology, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Masanori Taira
- Faculty of Science and Engineering, Chuo University, Tokyo, Japan
| | - Akira Suzuki
- Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
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Shu Y, Jin X, Ji M, Zhang Z, Wang X, Liang H, Lu S, Dong S, Lin Y, Guo Y, Zhuang Q, Wang Y, Lei Z, Guo L, Meng X, Zhou G, Zhang W, Chang L. Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis. Cancer Res 2024; 84:2836-2855. [PMID: 38862269 DOI: 10.1158/0008-5472.can-23-4034] [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: 12/19/2023] [Revised: 04/16/2024] [Accepted: 06/06/2024] [Indexed: 06/13/2024]
Abstract
Yes-associated protein (YAP) is a central player in cancer development, with functions extending beyond its recognized role in cell growth regulation. Recent work has identified a link between YAP/transcriptional coactivator with PDZ-binding motif (TAZ) and the DNA damage response. Here, we investigated the mechanistic underpinnings of the cross-talk between DNA damage repair and YAP activity. Ku70, a key component of the nonhomologous end joining pathway to repair DNA damage, engaged in a dynamic competition with TEAD4 for binding to YAP, limiting the transcriptional activity of YAP. Depletion of Ku70 enhanced interaction between YAP and TEAD4 and boosted YAP transcriptional capacity. Consequently, Ku70 loss enhanced tumorigenesis in colon cancer and hepatocellular carcinoma (HCC) in vivo. YAP impeded DNA damage repair and elevated genome instability by inducing PARP1 degradation through the SMURF2-mediated ubiquitin-proteasome pathway. Analysis of samples from patients with HCC substantiated the link between Ku70 expression, YAP activity, PARP1 levels, and genome instability. In conclusion, this research provides insight into the mechanistic interactions between YAP and key regulators of DNA damage repair, highlighting the role of a Ku70-YAP-PARP1 axis in preserving genome stability. Significance: Increased yes-associated protein transcriptional activity stimulated by loss of Ku70 induces PARP1 degradation by upregulating SMURF2 to inhibit DNA damage, driving genome instability and tumorigenesis.
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Affiliation(s)
- Yinyin Shu
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Xiaoni Jin
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Mintao Ji
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Zhisen Zhang
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Xiuxiu Wang
- Department of Anatomy, Wannan Medical College, Wuhu, China
| | - Haisheng Liang
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Shuangshuang Lu
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Shuai Dong
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yiping Lin
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yuhan Guo
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Qiuyu Zhuang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Yuhong Wang
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhe Lei
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lingchuan Guo
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuanyu Meng
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Guangming Zhou
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Wensheng Zhang
- Suzhou Medical College of Soochow University, Suzhou, China
| | - Lei Chang
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
- Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China
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8
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Domingues N, Calcagni’ A, Pires J, Freire SR, Herz NJ, Huynh T, Wieciorek K, Moreno MJ, Outeiro TF, Girão H, Milosevic I, Ballabio A, Raimundo N. Loss of the lysosomal protein CLN3 modifies the lipid content of the nuclear envelope leading to DNA damage and activation of YAP1 pro-apoptotic signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.31.596474. [PMID: 38853929 PMCID: PMC11160784 DOI: 10.1101/2024.05.31.596474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Batten disease is characterized by early-onset blindness, juvenile dementia and death during the second decade of life. The most common genetic causes are mutations in the CLN3 gene encoding a lysosomal protein. There are currently no therapies targeting the progression of the disease, mostly due to the lack of knowledge about the disease mechanisms. To gain insight into the impact of CLN3 loss on cellular signaling and organelle function, we generated CLN3 knock-out cells in a human cell line (CLN3-KO), and performed RNA sequencing to obtain the cellular transcriptome. Following a multi-dimensional transcriptome analysis, we identified the transcriptional regulator YAP1 as a major driver of the transcriptional changes observed in CLN3-KO cells. We further observed that YAP1 pro-apoptotic signaling is hyperactive as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of CLN3exΔ7/8 mice, an established model of Batten disease. Loss of CLN3 activates YAP1 by a cascade of events that starts with the inability of releasing glycerophosphodiesthers from CLN3-KO lysosomes, which leads to perturbations in the lipid content of the nuclear envelope and nuclear dysmorphism. This results in increased number of DNA lesions, activating the kinase c-Abl, which phosphorylates YAP1, stimulating its pro-apoptotic signaling. Altogether, our results highlight a novel organelle crosstalk paradigm in which lysosomal metabolites regulate nuclear envelope content, nuclear shape and DNA homeostasis. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may open new c-Abl-centric therapeutic strategies to target Batten disease.
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Affiliation(s)
- Neuza Domingues
- Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
| | - Alessia Calcagni’
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Joana Pires
- Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
| | - Sofia Roque Freire
- Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
| | - Niculin Joachim Herz
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA
| | - Tuong Huynh
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA
| | - Katarzyna Wieciorek
- University Medical Center Göttingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Göttingen, Germany
| | - Maria João Moreno
- CQC-Biological Chemistry Group, Chemistry Department FCTUC, Coimbra, Portugal
| | - Tiago Fleming Outeiro
- University Medical Center Göttingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Göttingen, Germany
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany
| | - Henrique Girão
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Centre for Innovative Biomedicine and Biotechnology, Academic and Clinical Center of Coimbra, Faculty of Medicine, University of Coimbra, Portugal
| | - Ira Milosevic
- Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
- Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, UK
| | - Andrea Ballabio
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA
- SSM School for Advanced Studies, Federico II University, Naples, Italy
| | - Nuno Raimundo
- Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
- Penn State Cancer Institute, Hershey, PA, USA
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9
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Kim G, Bhattarai PY, Lim SC, Lee KY, Choi HS. Sirtuin 5-mediated deacetylation of TAZ at K54 promotes melanoma development. Cell Oncol (Dordr) 2024; 47:967-985. [PMID: 38112979 DOI: 10.1007/s13402-023-00910-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] [Accepted: 12/04/2023] [Indexed: 12/21/2023] Open
Abstract
PURPOSE Nuclear accumulation of YAP/TAZ promotes tumorigenesis in several cancers, including melanoma. Although the mechanisms underlying the nuclear retention of YAP are known, those underlying the retention of TAZ remain unclear. Our study investigates a novel acetylation/deacetylation switch in TAZ, governing its subcellular localization in melanoma tumorigenesis. METHODS Immunoprecipitation/Western blot assessed TAZ protein interactions and acetylation. SIRT5 activity was quantified with enzyme-linked immunosorbent assay. Immunofluorescence indicated TAZ nuclear localization. TEAD transcriptional activity was measured through luciferase reporter assays. ChIP detected TAZ binding to the CTGF promoter. Transwell and wound healing assays quantified melanoma cell invasiveness and migration. Metastasis was evaluated using a mouse model via tail vein injections. Clinical relevance was explored via immunohistochemical staining of patient tumors. RESULTS CBP facilitated TAZ acetylation at K54 in response to epidermal growth factor stimulation, while SIRT5 mediated deacetylation. Acetylation correlated with phosphorylation, regulating TAZ's binding with LATS2 or TEAD. TAZ K54 acetylation enhanced its S89 phosphorylation, promoting cytosolic retention via LATS2 interaction. SIRT5-mediated deacetylation enhanced TAZ-TEAD interaction and nuclear retention. Chromatin IP showed SIRT5-deacetylated TAZ recruited to CTGF promoter, boosting transcriptional activity. In a mouse model, SIRT5 overexpression induced melanoma metastasis to lung tissue following the injection of B16F10 melanocytes via the tail vein, and this effect was prevented by verteporfin treatment. CONCLUSIONS Our study revealed a novel mechanism of TAZ nuclear retention regulated by SIRT5-mediated K54 deacetylation and demonstrated the significance of TAZ deacetylation in CTGF expression. This study highlights the potential implications of the SIRT5/TAZ axis for treating metastatic melanoma.
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Affiliation(s)
- Garam Kim
- College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, Republic of Korea
| | - Poshan Yugal Bhattarai
- College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, Republic of Korea
| | - Sung-Chul Lim
- Department of Pathology, School of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Kwang Youl Lee
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Hong Seok Choi
- College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, Republic of Korea.
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10
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Parrish AG, Arora S, Thirimanne HN, Rudoy D, Schmid S, Sievers P, Sahm F, Holland EC, Szulzewsky F. Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.30.596719. [PMID: 38854109 PMCID: PMC11160807 DOI: 10.1101/2024.05.30.596719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset of meningiomas is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.
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Affiliation(s)
- Abigail G Parrish
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | - Sonali Arora
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | | | - Dmytro Rudoy
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | - Sebastian Schmid
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | - Philipp Sievers
- Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Felix Sahm
- Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
| | - Eric C Holland
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Seattle Translational Tumor Research Center, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | - Frank Szulzewsky
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
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11
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Slaninová V, Heron-Milhavet L, Robin M, Jeanson L, Aissanou A, Kantar D, Tosi D, Bréhélin L, Gongora C, Djiane A. The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells. BMC Cancer 2024; 24:587. [PMID: 38741073 PMCID: PMC11092100 DOI: 10.1186/s12885-024-12316-4] [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: 09/25/2023] [Accepted: 04/29/2024] [Indexed: 05/16/2024] Open
Abstract
YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.
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Affiliation(s)
- Věra Slaninová
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | | | - Mathilde Robin
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
- LIRMM, Univ Montpellier, Inserm, CNRS, Montpellier, France
- Fondazione Gianni Bonadonna, Milan, Italy
| | - Laura Jeanson
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Adam Aissanou
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Diala Kantar
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Diego Tosi
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
- Fondazione Gianni Bonadonna, Milan, Italy
| | | | - Céline Gongora
- IRCM, Univ Montpellier, Inserm, ICM, CNRS, Montpellier, France.
| | - Alexandre Djiane
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France.
- IRCM, Univ Montpellier, Inserm, ICM, CNRS, Montpellier, France.
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12
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Tang Y, Yuan Z, Lu X, Song Y, Zhu S, Qiu C, zhang Q, Fu B, Jia C, Li H. RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway. J Clin Transl Hepatol 2024; 12:357-370. [PMID: 38638379 PMCID: PMC11022058 DOI: 10.14218/jcth.2023.00339] [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: 07/27/2023] [Revised: 01/03/2024] [Accepted: 02/02/2024] [Indexed: 04/20/2024] Open
Abstract
Background and Aims Hepatic ischemia-reperfusion injury (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aimed to investigate the pathogenesis of RAMP1 in HIRI. Methods We established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hypoxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function. Results Liver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experiments. Conclusions Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.
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Affiliation(s)
- Yongsheng Tang
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zenan Yuan
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xu Lu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yingqiu Song
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuguang Zhu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chunhui Qiu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qi zhang
- Department of Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Binsheng Fu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Changchang Jia
- Department of Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hua Li
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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13
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Zhao Y, Sheldon M, Sun Y, Ma L. New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer. Cancers (Basel) 2023; 15:5497. [PMID: 38067201 PMCID: PMC10705714 DOI: 10.3390/cancers15235497] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/07/2023] [Accepted: 11/17/2023] [Indexed: 02/12/2024] Open
Abstract
The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ's biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field.
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Affiliation(s)
- Yang Zhao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Y.Z.); (M.S.)
| | - Marisela Sheldon
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Y.Z.); (M.S.)
| | - Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Y.Z.); (M.S.)
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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14
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Kofler M, Kapus A. Nuclear Import and Export of YAP and TAZ. Cancers (Basel) 2023; 15:4956. [PMID: 37894323 PMCID: PMC10605228 DOI: 10.3390/cancers15204956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/05/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Yes-associated Protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding Motif (TAZ) are major regulators of gene transcription/expression, primarily controlled by the Hippo pathway and the cytoskeleton. Integrating an array of chemical and mechanical signals, they impact growth, differentiation, and regeneration. Accordingly, they also play key roles in tumorigenesis and metastasis formation. Their activity is primarily regulated by their localization, that is, Hippo pathway- and/or cytoskeleton-controlled cytosolic or nuclear sequestration. While many details of such prevailing retention models have been elucidated, much less is known about their actual nuclear traffic: import and export. Although their size is not far from the cutoff for passive diffusion through the nuclear pore complex (NPC), and they do not contain any classic nuclear localization (NLS) or nuclear export signal (NES), evidence has been accumulating that their shuttling involves mediated and thus regulatable/targetable processes. The aim of this review is to summarize emerging information/concepts about their nucleocytoplasmic shuttling, encompassing the relevant structural requirements (NLS, NES), nuclear transport receptors (NTRs, karyophererins), and NPC components, along with the potential transport mechanisms and their regulation. While dissecting retention vs. transport is often challenging, the emerging picture suggests that YAP/TAZ shuttles across the NPC via multiple, non-exclusive, mediated mechanisms, constituting a novel and intriguing facet of YAP/TAZ biology.
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Affiliation(s)
- Michael Kofler
- Keenan Research Centre for Biomedical Science of the St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada;
| | - András Kapus
- Keenan Research Centre for Biomedical Science of the St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada;
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON M5B 1T8, Canada
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15
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El Yousfi Y, Mora-Molina R, López-Rivas A, Yerbes R. Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells. Cells 2023; 12:2370. [PMID: 37830584 PMCID: PMC10571597 DOI: 10.3390/cells12192370] [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: 08/31/2023] [Revised: 09/19/2023] [Accepted: 09/25/2023] [Indexed: 10/14/2023] Open
Abstract
Different studies have reported that inhibiting the mevalonate pathway with statins may increase the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although the signaling mechanism leading to this sensitization remains largely unknown. We investigated the role of the YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex in the metabolic control of TRAIL sensitivity by the mevalonate pathway. We show that depleting nuclear YAP/TAZ in tumor cells, either via treatment with statins or by silencing YAP/TAZ expression with siRNAs, facilitates the activation of apoptosis by TRAIL. Furthermore, the blockage of TEAD transcriptional activity either pharmacologically or through the ectopic expression of a disruptor of the YAP/TAZ interaction with TEAD transcription factors, overcomes the resistance of tumor cells to the induction of apoptosis by TRAIL. Our results show that the mevalonate pathway controls cellular the FLICE-inhibitory protein (cFLIP) expression in tumor cells. Importantly, inhibiting the YAP/TAZ-TEAD signaling pathway induces cFLIP down-regulation, leading to a marked sensitization of tumor cells to apoptosis induction by TRAIL. Our data suggest that a combined strategy of targeting TEAD activity and selectively activating apoptosis signaling by agonists of apoptotic TRAIL receptors could be explored as a potential therapeutic approach in cancer treatment.
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Affiliation(s)
- Younes El Yousfi
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain; (Y.E.Y.); (R.M.-M.); (A.L.-R.)
| | - Rocío Mora-Molina
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain; (Y.E.Y.); (R.M.-M.); (A.L.-R.)
| | - Abelardo López-Rivas
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain; (Y.E.Y.); (R.M.-M.); (A.L.-R.)
| | - Rosario Yerbes
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain; (Y.E.Y.); (R.M.-M.); (A.L.-R.)
- Medical Physiology and Biophysics Department, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS) (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla), 41013 Seville, Spain
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16
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Zhang CT, Qin DL, Cao XY, Kan JS, Huang XX, Gao DS, Gao J. Dephosphorylation of Six2Y129 protects tyrosine hydroxylase-positive cells in SNpc by regulating TEA domain 1 expression. iScience 2023; 26:107049. [PMID: 37534182 PMCID: PMC10391717 DOI: 10.1016/j.isci.2023.107049] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 04/03/2023] [Accepted: 06/01/2023] [Indexed: 08/04/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). We recently reported that Six2 could reverse the degeneration of DA neurons in a dephosphorylation state. Here we further identified that Eya1 was the phosphatase of Six2 that could dephosphorylate the tyrosine 129 (Y129) site by forming a complex with Six2 in damaged DA cells. Dephosphorylated Six2 then translocates from the cytoplasm to the nucleus. Using ChIP-qPCR and dual luciferase assay, we found that dephosphorylated Six2 down-regulates TEA domain1 (Tead1) expression, thus inhibiting 6-hydroxydopamine (6-OHDA)-induced apoptosis in DA cells. Furthermore, we showed Six2Y129F/Tead1 signaling could protect against the loss of SNpc tyrosine hydroxylase-positive (TH+) cells and improve motor function in PD model rats. Our results demonstrate a dephosphorylation-dependent mechanism of Six2 that restores the degeneration of DA neurons, which could represent a potential therapeutic target for PD.
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Affiliation(s)
- Can-tang Zhang
- Department of Respiratory and Critical Care, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Deng-li Qin
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Xia-yin Cao
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jia-shuo Kan
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Xin-xing Huang
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Dian-shuai Gao
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jin Gao
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
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Luo J, Deng L, Zou H, Guo Y, Tong T, Huang M, Ling G, Li P. New insights into the ambivalent role of YAP/TAZ in human cancers. J Exp Clin Cancer Res 2023; 42:130. [PMID: 37211598 DOI: 10.1186/s13046-023-02704-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/10/2023] [Indexed: 05/23/2023] Open
Abstract
Hippo signaling was first identified in Drosophila as a key controller of organ size by regulating cell proliferation and anti-apoptosis. Subsequent studies have shown that this pathway is highly conserved in mammals, and its dysregulation is implicated in multiple events of cancer development and progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (hereafter YAP/TAZ) are the downstream effectors of the Hippo pathway. YAP/TAZ overexpression or activation is sufficient to induce tumor initiation and progression, as well as recurrence and therapeutic resistance. However, there is growing evidence that YAP/TAZ also exert a tumor-suppressive function in a context-dependent manner. Therefore, caution should be taken when targeting Hippo signaling in clinical trials in the future. In this review article, we will first give an overview of YAP/TAZ and their oncogenic roles in various cancers and then systematically summarize the tumor-suppressive functions of YAP/TAZ in different contexts. Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based tumor targeted therapy and potential future directions.
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Affiliation(s)
- Juan Luo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Liang Deng
- Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Hailin Zou
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Yibo Guo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Tongyu Tong
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Mingli Huang
- Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Gengqiang Ling
- Department of Neurosurgery, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Peng Li
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China.
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Ryabchenko B, Šroller V, Horníková L, Lovtsov A, Forstová J, Huérfano S. The interactions between PML nuclear bodies and small and medium size DNA viruses. Virol J 2023; 20:82. [PMID: 37127643 PMCID: PMC10152602 DOI: 10.1186/s12985-023-02049-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 04/23/2023] [Indexed: 05/03/2023] Open
Abstract
Promyelocytic leukemia nuclear bodies (PM NBs), often referred to as membraneless organelles, are dynamic macromolecular protein complexes composed of a PML protein core and other transient or permanent components. PML NBs have been shown to play a role in a wide variety of cellular processes. This review describes in detail the diverse and complex interactions between small and medium size DNA viruses and PML NBs that have been described to date. The PML NB components that interact with small and medium size DNA viruses include PML protein isoforms, ATRX/Daxx, Sp100, Sp110, HP1, and p53, among others. Interaction between viruses and components of these NBs can result in different outcomes, such as influencing viral genome expression and/or replication or impacting IFN-mediated or apoptotic cell responses to viral infection. We discuss how PML NB components abrogate the ability of adenoviruses or Hepatitis B virus to transcribe and/or replicate their genomes and how papillomaviruses use PML NBs and their components to promote their propagation. Interactions between polyomaviruses and PML NBs that are poorly understood but nevertheless suggest that the NBs can serve as scaffolds for viral replication or assembly are also presented. Furthermore, complex interactions between the HBx protein of hepadnaviruses and several PML NBs-associated proteins are also described. Finally, current but scarce information regarding the interactions of VP3/apoptin of the avian anellovirus with PML NBs is provided. Despite the considerable number of studies that have investigated the functions of the PML NBs in the context of viral infection, gaps in our understanding of the fine interactions between viruses and the very dynamic PML NBs remain. The complexity of the bodies is undoubtedly a great challenge that needs to be further addressed.
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Affiliation(s)
- Boris Ryabchenko
- Department of Genetics and Microbiology, Faculty of Science, BIOCEV, Charles University, Vestec, 25250, Czech Republic
| | - Vojtěch Šroller
- Department of Genetics and Microbiology, Faculty of Science, BIOCEV, Charles University, Vestec, 25250, Czech Republic
| | - Lenka Horníková
- Department of Genetics and Microbiology, Faculty of Science, BIOCEV, Charles University, Vestec, 25250, Czech Republic
| | - Alexey Lovtsov
- Department of Genetics and Microbiology, Faculty of Science, BIOCEV, Charles University, Vestec, 25250, Czech Republic
| | - Jitka Forstová
- Department of Genetics and Microbiology, Faculty of Science, BIOCEV, Charles University, Vestec, 25250, Czech Republic
| | - Sandra Huérfano
- Department of Genetics and Microbiology, Faculty of Science, BIOCEV, Charles University, Vestec, 25250, Czech Republic.
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Ghosh I, Khalil MI, Mirza R, King J, Olatunde D, De Benedetti A. NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression. Biomedicines 2023; 11:biomedicines11030734. [PMID: 36979713 PMCID: PMC10045622 DOI: 10.3390/biomedicines11030734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/13/2023] [Accepted: 02/20/2023] [Indexed: 03/04/2023] Open
Abstract
The key to preventing mCRPC progression is understanding how androgen-dependent PCa cells progress to independence and modify their transcriptional repertoire accordingly. We recently identified a novel axis of the Hippo pathway characterized by the sequential kinase cascade induced by androgen deprivation, AR−>TLK1B>NEK1>pYAP1-Y407, leading to CRPC adaptation. Phosphorylation of YAP1-Y407 increases upon ADT or induction of DNA damage, correlated with the known increase in NEK1 expression/activity, and this is suppressed in the Y407F mutant. Dominant expression of YAP1-Y407F in Hek293 cells reprograms the YAP1-mediated transcriptome to reduce TEAD- and p73-regulated gene expression and mediates sensitivity to MMC. NEK1 haploinsufficient TRAMP mice display reduced YAP1 expression and, if castrated, fail to progress to overt prostate carcinomas, even while displaying reduced E-Cadherin (E-Cad) expression in hyperplastic ductules. YAP1 overexpression, but not the Y407F mutant, transforms LNCaP cells to androgen-independent growth with a mesenchymal morphology. Immunohistochemical examination of prostate cancer biopsies revealed that the pYAP1-Y407 nuclear signal is low in samples of low-grade cancer but elevated in high GS specimens. We also found that J54, a pharmacological inhibitor of the TLK1>NEK1>YAP1 nexus leading to degradation of YAP1, can suppress the transcriptional reprogramming of LNCaP cells to androgen-independent growth and EMT progression, even when YAP1-WT is overexpressed.
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Affiliation(s)
- Ishita Ghosh
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Md Imtiaz Khalil
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Rusella Mirza
- Department of Pathology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Judy King
- Department of Pathology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Damilola Olatunde
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Arrigo De Benedetti
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
- Correspondence:
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20
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Zhang C, Li Y, Chakraborty A, Li Y, Rebello KR, Ren P, Luo W, Zhang L, Lu HS, Cassis LA, Coselli JS, Daugherty A, LeMaire SA, Shen YH. Aortic Stress Activates an Adaptive Program in Thoracic Aortic Smooth Muscle Cells That Maintains Aortic Strength and Protects Against Aneurysm and Dissection in Mice. Arterioscler Thromb Vasc Biol 2023; 43:234-252. [PMID: 36579645 PMCID: PMC9877188 DOI: 10.1161/atvbaha.122.318135] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 12/08/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD). METHODS We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct effects of YAP (yes-associated protein) on the SMC adaptive response in vitro. The role of YAP in AAD development was further evaluated in AngII-infused mice with SMC-specific Yap deletion. RESULTS In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by upregulated genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and PI3K-PKB/Akt (phosphoinositide-3-kinase-protein kinase B/Akt) and TGF-β (transforming growth factor beta) signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/transcriptional enhanced associate domains as a top candidate transcription complex driving the expression of these genes (eg, Lox, Col5a2, Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to adaptive gene regulatory regions (eg, Lox) and increased their transcript abundance. SMC-specific Yap deletion in mice compromised this adaptive response in SMCs, leading to an increased AAD incidence. CONCLUSIONS Aortic stress triggers the systemic epigenetic induction of an adaptive response (eg, wound healing, proliferation, matrix organization) in thoracic aortic SMCs that depends on functional biomechanical signal transduction (eg, YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing AAD in mice.
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Affiliation(s)
- Chen Zhang
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Yanming Li
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Abhijit Chakraborty
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Yang Li
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Kimberly R Rebello
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Pingping Ren
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Wei Luo
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Lin Zhang
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Hong S Lu
- Saha Cardiovascular Research Center (H.S.L., A.D.), University of Kentucky, Lexington
- Department of Physiology (H.S.L., A.D.), University of Kentucky, Lexington
| | - Lisa A Cassis
- Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington
| | - Joseph S Coselli
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (J.S.C., S.A.L., Y.S.)
| | - Alan Daugherty
- Saha Cardiovascular Research Center (H.S.L., A.D.), University of Kentucky, Lexington
- Department of Physiology (H.S.L., A.D.), University of Kentucky, Lexington
| | - Scott A LeMaire
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (J.S.C., S.A.L., Y.S.)
| | - Ying H Shen
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (J.S.C., S.A.L., Y.S.)
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21
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Calses PC, Pham VC, Guarnaccia AD, Choi M, Verschueren E, Bakker ST, Pham TH, Hinkle T, Liu C, Chang MT, Kljavin N, Bakalarski C, Haley B, Zou J, Yan C, Song X, Lin X, Rowntree R, Ashworth A, Dey A, Lill JR. TEAD Proteins Associate With DNA Repair Proteins to Facilitate Cellular Recovery From DNA Damage. Mol Cell Proteomics 2023; 22:100496. [PMID: 36640924 PMCID: PMC9947421 DOI: 10.1016/j.mcpro.2023.100496] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/15/2022] [Accepted: 01/04/2023] [Indexed: 01/13/2023] Open
Abstract
Transcriptional enhanced associate domain family members 1 to 4 (TEADs) are a family of four transcription factors and the major transcriptional effectors of the Hippo pathway. In order to activate transcription, TEADs rely on interactions with other proteins, such as the transcriptional effectors Yes-associated protein and transcriptional co-activator with PDZ-binding motif. Nuclear protein interactions involving TEADs influence the transcriptional regulation of genes involved in cell growth, tissue homeostasis, and tumorigenesis. Clearly, protein interactions for TEADs are functionally important, but the full repertoire of TEAD interaction partners remains unknown. Here, we employed an affinity purification mass spectrometry approach to identify nuclear interacting partners of TEADs. We performed affinity purification mass spectrometry experiment in parallel in two different cell types and compared a wildtype TEAD bait protein to a nuclear localization sequence mutant that does not localize to the nucleus. We quantified the results using SAINT analysis and found a significant enrichment of proteins linked to DNA damage including X-ray repair cross-complementing protein 5 (XRCC5), X-ray repair cross-complementing protein 6 (XRCC6), poly(ADP-ribose) polymerase 1 (PARP1), and Rap1-interacting factor 1 (RIF1). In cellular assays, we found that TEADs co-localize with DNA damage-induced nuclear foci marked by histone H2AX phosphorylated on S139 (γH2AX) and Rap1-interacting factor 1. We also found that depletion of TEAD proteins makes cells more susceptible to DNA damage by various agents and that depletion of TEADs promotes genomic instability. Additionally, depleting TEADs dampens the efficiency of DNA double-stranded break repair in reporter assays. Our results connect TEADs to DNA damage response processes, positioning DNA damage as an important avenue for further research of TEAD proteins.
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Affiliation(s)
- Philamer C Calses
- Departments of Discovery Oncology, Genentech Inc, South San Francisco, California, USA; Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc, South San Francisco, California, USA
| | - Victoria C Pham
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc, South San Francisco, California, USA
| | - Alissa D Guarnaccia
- Departments of Discovery Oncology, Genentech Inc, South San Francisco, California, USA; Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc, South San Francisco, California, USA
| | - Meena Choi
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc, South San Francisco, California, USA
| | - Erik Verschueren
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc, South San Francisco, California, USA
| | - Sietske T Bakker
- UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | - Trang H Pham
- Departments of Discovery Oncology, Genentech Inc, South San Francisco, California, USA
| | - Trent Hinkle
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc, South San Francisco, California, USA
| | - Chad Liu
- Departments of Discovery Oncology, Genentech Inc, South San Francisco, California, USA
| | - Matthew T Chang
- Department of Bioinformatics, Genentech Inc, South San Francisco, California, USA
| | - Noelyn Kljavin
- Department of Molecular Oncology, Genentech Inc, South San Francisco, California, USA
| | - Corey Bakalarski
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc, South San Francisco, California, USA
| | - Benjamin Haley
- Departments of Discovery Oncology, Genentech Inc, South San Francisco, California, USA
| | - Jianing Zou
- Department of Biology, Research Service Division, WuXi AppTec, Shanghai, China
| | - Cuicui Yan
- Department of Biology, Research Service Division, WuXi AppTec, Shanghai, China
| | - Xia Song
- Department of Biology, Research Service Division, WuXi AppTec, Shanghai, China
| | - Xiaoyan Lin
- Department of Biology, Research Service Division, WuXi AppTec, Shanghai, China
| | - Rebecca Rowntree
- Department of Molecular Oncology, Genentech Inc, South San Francisco, California, USA
| | - Alan Ashworth
- UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | - Anwesha Dey
- Departments of Discovery Oncology, Genentech Inc, South San Francisco, California, USA.
| | - Jennie R Lill
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc, South San Francisco, California, USA.
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22
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Messina B, Lo Sardo F, Scalera S, Memeo L, Colarossi C, Mare M, Blandino G, Ciliberto G, Maugeri-Saccà M, Bon G. Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression. Cell Death Dis 2023; 14:21. [PMID: 36635265 PMCID: PMC9837097 DOI: 10.1038/s41419-023-05568-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/27/2022] [Accepted: 01/06/2023] [Indexed: 01/13/2023]
Abstract
The Hippo pathway plays a critical role for balancing proliferation and differentiation, thus regulating tissue homeostasis. The pathway acts through a kinase cascade whose final effectors are the Yes-associated protein (YAP) and its paralog transcriptional co‑activator with PDZ‑binding motif (TAZ). In response to a variety of upstream signals, YAP and TAZ activate a transcriptional program that modulates cellular proliferation, tissue repair after injury, stem cell fate decision, and cytoskeletal reorganization. Hippo pathway signaling is often dysregulated in gastric cancer and in Helicobacter pylori-induced infection, suggesting a putative role of its deregulation since the early stages of the disease. In this review, we summarize the architecture and regulation of the Hippo pathway and discuss how its dysregulation fuels the onset and progression of gastric cancer. In this setting, we also focus on the crosstalk between Hippo and other established oncogenic signaling pathways. Lastly, we provide insights into the therapeutic approaches targeting aberrant YAP/TAZ activation and discuss the related clinical perspectives and challenges.
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Affiliation(s)
- Beatrice Messina
- Clinical Trial Center, Biostatistics and Bioinformatics Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Federica Lo Sardo
- Oncogenomic and Epigenetic Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Stefano Scalera
- SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Lorenzo Memeo
- Pathology Unit, Mediterranean Institute of Oncology, Viagrande, Italy
| | | | - Marzia Mare
- Medical Oncology Unit, Mediterranean Institute of Oncology, Viagrande, Italy
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Gennaro Ciliberto
- Scientific Directorate, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marcello Maugeri-Saccà
- Clinical Trial Center, Biostatistics and Bioinformatics Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giulia Bon
- Cellular Network and Molecular Therapeutic Target Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
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23
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Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside. Biomedicines 2022; 10:biomedicines10102512. [PMID: 36289774 PMCID: PMC9599207 DOI: 10.3390/biomedicines10102512] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 12/24/2022] Open
Abstract
The Hippo pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration under physiological conditions, and its aberrations have been well studied to promote tumor initiation and progression. Dysregulation of the Hippo tumor suppressor signaling frequently occurs in gastric cancer (GC) and other solid tumors and contributes to cancer development through modulating multiple aspects, including cell proliferation, survival, metastasis, and oncotherapy resistance. In the clinic, Hippo components also possess diagnostic and prognostic values for cancer patients. Considering its crucial role in driving tumorigenesis, targeting the Hippo pathway may greatly benefit developing novel cancer therapies. This review summarizes the current research progress regarding the core components and regulation of the Hippo pathway, as well as the mechanism and functional roles of their dysregulation in gastrointestinal malignancies, especially in GC, and discusses the therapeutic potential of targeting the Hippo pathway against cancers.
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24
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Wang Y, Chen H, Yu J, Kang W, To KF. Recent insight into the role and therapeutic potential of YAP/TAZ in gastrointestinal cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188787. [PMID: 36041574 DOI: 10.1016/j.bbcan.2022.188787] [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: 06/06/2022] [Revised: 07/25/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022]
Abstract
With the rapid development of cancer treatment, gastrointestinal (GI) cancers are still the most prevalent malignancies with high morbidity and mortality worldwide. Dysregulation of the Hippo signaling pathway has been recognized to play a critical role during cancer development and adopted for monitoring disease progression and therapy response. Despite the well-documented tumor proliferation and metastasis, recent efforts in two core Hippo components, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), have identified as the driving forces behind cancer metabolism, stemness, tumor immunity, and therapy resistance. Understanding the molecular mechanisms by which YAP/TAZ facilitates the tumorigenesis and progression of GI cancer, and identifying novel therapeutic strategies for targeting YAP/TAZ are crucial to GI cancer treatment and prevention. In this study, we summarize the latest findings on the function and regulatory mechanisms of YAP/TAZ in GI cancers, and highlight the translational significance of targeting YAP/TAZ for cancer therapies.
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Affiliation(s)
- Yifei Wang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Huarong Chen
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
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La Verde G, Artiola V, Pugliese M, La Commara M, Arrichiello C, Muto P, Netti PA, Fusco S, Panzetta V. Radiation therapy affects YAP expression and intracellular localization by modulating lamin A/C levels in breast cancer. Front Bioeng Biotechnol 2022; 10:969004. [PMID: 36091449 PMCID: PMC9450017 DOI: 10.3389/fbioe.2022.969004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
The microenvironment of breast cancer actively participates in tumorigenesis and cancer progression. The changes observed in the architecture of the extracellular matrix initiate an oncogene-mediated cell reprogramming, that leads to a massive triggering of YAP nuclear entry, and, therefore, to cancer cell proliferation, invasion and probably to increased radiation-resistance. However, it is not yet fully understood how radiotherapy regulates the expression and subcellular localization of YAP in breast cancer cells experiencing different microenvironmental stiffnesses. To elucidate the role of extracellular matrix stiffness and ionizing radiations on YAP regulation, we explored the behaviour of two different mammary cell lines, a normal epithelial cell line (MCF10A) and a highly aggressive and invasive adenocarcinoma cell line (MDA-MB-231) interacting with polyacrylamide substrates mimicking the mechanics of both normal and tumour tissues (∼1 and ∼13 kPa). We report that X-ray radiation affected in a significant way the levels of YAP expression, density, and localization in both cell lines. After 24 h, MCF10A and MDA-MB-231 increased the expression level of YAP in both nucleus and cytoplasm in a dose dependent manner and particularly on the stiffer substrates. After 72 h, MCF10A reduced mostly the YAP expression in the cytoplasm, whereas it remained high in the nucleus of cells on stiffer substrates. Tumour cells continued to exhibit higher levels of YAP expression, especially in the cytoplasmic compartment, as indicated by the reduction of nuclear/cytoplasmic ratio of total YAP. Then, we investigated the existence of a correlation between YAP localization and the expression of the nuclear envelope protein lamin A/C, considering its key role in modulating nuclear deformability and changes in YAP shuttling phenomena. As supposed, we found that the effects of radiation on YAP nucleus/cytoplasmic expression ratio, increasing in healthy cells and decreasing in tumour ones, were accompanied by lower and higher lamin A/C levels in MCF10A and MDA-MB-231 cells, respectively. These findings point to obtain a deeper knowledge of the role of the extracellular matrix and the effects of X-rays on YAP and lamin A/C expression that can be used in the design of doses and timing of radiation therapy.
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Affiliation(s)
- Giuseppe La Verde
- Istituto Nazionale di Fisica Nucleare, INFN Sezione di Napoli, Naples, Italy
- Dipartimento di Farmacia, Università Degli Studi di Napoli Federico II, Naples, Italy
| | - Valeria Artiola
- Dipartimento di Fisica “Ettore Pancini”, Università Degli Studi di Napoli Federico II, Naples, Italy
| | - Mariagabriella Pugliese
- Istituto Nazionale di Fisica Nucleare, INFN Sezione di Napoli, Naples, Italy
- Dipartimento di Fisica “Ettore Pancini”, Università Degli Studi di Napoli Federico II, Naples, Italy
| | - Marco La Commara
- Istituto Nazionale di Fisica Nucleare, INFN Sezione di Napoli, Naples, Italy
- Dipartimento di Farmacia, Università Degli Studi di Napoli Federico II, Naples, Italy
| | - Cecilia Arrichiello
- Radiotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione “G. Pascale”, Naples, Italy
| | - Paolo Muto
- Radiotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione “G. Pascale”, Naples, Italy
| | - Paolo A. Netti
- Interdisciplinary Research Centre on Biomaterials (CRIB) and Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale, Università Degli Studi di Napoli Federico II, Naples, Italy
- Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia, Naples, Italy
| | - Sabato Fusco
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy
- *Correspondence: Sabato Fusco,
| | - Valeria Panzetta
- Interdisciplinary Research Centre on Biomaterials (CRIB) and Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale, Università Degli Studi di Napoli Federico II, Naples, Italy
- Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia, Naples, Italy
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Liu WW, Wang F, Li C, Song XY, Otkur W, Zhu YY, Hayashi T, Mizuno K, Hattori S, Fujisaki H, Ikejima T. Silibinin relieves UVB-induced apoptosis of human skin cells by inhibiting the YAP-p73 pathway. Acta Pharmacol Sin 2022; 43:2156-2167. [PMID: 34912007 PMCID: PMC9343358 DOI: 10.1038/s41401-021-00826-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/16/2021] [Indexed: 02/07/2023]
Abstract
Excessive exposure to UVB induces skin diseases. Silibinin, a flavonolignan used for treating liver diseases, is found to be effective against UVB-caused skin epidermal and dermal cell damage. In this study we investigated the molecular mechanisms underlying. Human nonmalignant immortalized keratinocyte HaCaT cells and neonatal human foreskin fibroblasts HFFs were exposed to UVB irradiation. We showed that pre-treatment with silibinin dose-dependently decreased UVB-induced apoptosis of HaCaT cells. Furthermore, we showed that silibinin treatment inhibited nuclear translocation of YAP after UVB irradiation. Molecular docking analysis and DARTS assay confirmed the direct interaction of silibinin with YAP. Silencing YAP by siRNA had no influence on the survival of HaCaT cells, whereas inhibiting classical YAP-TEAD signaling pathway by siRNA targeting TEAD1 or its pharmaceutical inhibitor verteporfin further augmented UVB-induced apoptosis, suggesting that YAP-TEAD pathway was prosurvival, which did not participate in the protective effect of silibinin. We then explored the pro-apoptotic YAP-p73 pathway. p73 was upregulated in UVB-irradiated cells, but reduced by silibinin cotreatment. The mRNA and protein levels of p73 target genes (PML, p21 and Bax) were all increased by UVB but decreased by silibinin co-treatment. Inhibiting p73 by using siRNA reduced UVB-induced apoptosis, suggesting that downregulation of p73 was responsible for the cytoprotective effect of silibinin. In HFFs, the upregulated YAP-p73 pathway by UVB irradiation was also suppressed by silibinin. Collectively, YAP-p73 pathway is a major cause of the death of UVB-exposed epidermal HaCaT cells and dermal HFFs. Silibinin directly inhibits YAP-p73 pathway, exerting the protective action on UVB-irradiated skin cells.
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Affiliation(s)
- Wei-wei Liu
- grid.412561.50000 0000 8645 4345Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016 China
| | - Fang Wang
- grid.412561.50000 0000 8645 4345Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016 China
| | - Can Li
- grid.412561.50000 0000 8645 4345Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016 China
| | - Xiao-yu Song
- grid.412561.50000 0000 8645 4345Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016 China
| | - Wuxiyar Otkur
- grid.412561.50000 0000 8645 4345Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016 China ,grid.423905.90000 0004 1793 300XCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023 China
| | - Yu-ying Zhu
- grid.412561.50000 0000 8645 4345Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016 China
| | - Toshihiko Hayashi
- grid.412561.50000 0000 8645 4345Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016 China ,grid.411110.40000 0004 1793 1012Department of Chemistry and Life science, School of Advanced Engineering, Kogakuin University, 2665-1, Nakanomachi, Hachioji, Tokyo 192-0015 Japan ,Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017 Japan
| | - Kazunori Mizuno
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017 Japan
| | - Shunji Hattori
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017 Japan
| | - Hitomi Fujisaki
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017 Japan
| | - Takashi Ikejima
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China. .,Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Shenyang, 110016, China.
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YAP and TAZ: Monocorial and bicorial transcriptional co-activators in human cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188756. [PMID: 35777600 DOI: 10.1016/j.bbcan.2022.188756] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/09/2022] [Accepted: 06/23/2022] [Indexed: 12/17/2022]
Abstract
The transcriptional regulators YAP and TAZ are involved in numerous physiological processes including organ development, growth, immunity and tissue regeneration. YAP and TAZ dysregulation also contribute to tumorigenesis, thereby making them attractive cancer therapeutic targets. Arbitrarily, YAP and TAZ are often considered as a single protein, and are referred to as YAP/TAZ in most studies. However, increasing experimental evidences documented that YAP and TAZ perform both overlapping and distinct functions in several physiological and pathological processes. In addition to regulating distinct processes, YAP and TAZ are also regulated by distinct upstream cues. The aim of the review is to describe the distinct roles of YAP and TAZ focusing particularly on cancer. Therapeutic strategies targeting either YAP and TAZ proteins or only one of them should be carefully evaluated. Selective targeting of YAP or TAZ may in fact impair different pathways and determine diverse clinical outputs.
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Sheng H, Hao Z, Zhu L, Zeng Y, He J. Construction and validation of a two-gene signature based on SUMOylation regulatory genes in non-small cell lung cancer patients. BMC Cancer 2022; 22:572. [PMID: 35606717 PMCID: PMC9125860 DOI: 10.1186/s12885-022-09575-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 04/18/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Post-translational modification plays an important role in the occurrence and development of various tumors. However, few researches were focusing on the SUMOylation regulatory genes as tumor biomarkers to predict the survival for specific patients. Here, we constructed and validated a two-gene signature to predict the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. METHODS The datasets analyzed in this study were downloaded from TCGA and GEO databases. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to construct the two-gene signature. Gene set enrichment analysis (GSEA) and Gene Ontology (GO) was used to identify hub pathways associated with risk genes. The CCK-8 assay, cell cycle analysis, and transwell assay was used to validate the function of risk genes in NSCLC cell lines. RESULTS Firstly, most of the SUMOylation regulatory genes were highly expressed in various tumors through the R package 'limma' in the TCGA database. Secondly, our study found that the two gene signature constructed by LASSO regression analysis, as an independent prognostic factor, could predict the OS in both the TCGA training cohort and GEO validation cohorts (GSE68465, GSE37745, and GSE30219). Furthermore, functional enrichment analysis suggests that high-risk patients defined by the risk score system were associated with the malignant phenomenon, such as DNA replication, cell cycle regulation, p53 signaling pathway. Finally, the results of the CCK-8 assay, cell cycle analysis, and transwell assay demonstrated that the two risk genes, SAE1 and UBA2, could promote proliferation and migration in non-small cell lung cancer cells. CONCLUSIONS The two-gene signature constructed in our study could predict the OS and may provide valuable clinical guidance for the treatment of NSCLC patients.
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Affiliation(s)
- Hongxu Sheng
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, China National Center for Respiratory Medicine, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China
| | - Zhexue Hao
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, China National Center for Respiratory Medicine, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China
| | - Linhai Zhu
- Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, Hangzhou, China
| | - Yuan Zeng
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, China National Center for Respiratory Medicine, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China
| | - Jianxing He
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, China National Center for Respiratory Medicine, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China.
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29
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Sinclear CK, Maruyama J, Nagashima S, Arimoto‐Matsuzaki K, Kuleape JA, Iwasa H, Nishina H, Hata Y. Protein kinase Cα activation switches YAP1 from TEAD-mediated signaling to p73-mediated signaling. Cancer Sci 2022; 113:1305-1320. [PMID: 35102644 PMCID: PMC8990296 DOI: 10.1111/cas.15285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/20/2022] [Accepted: 01/22/2022] [Indexed: 12/30/2022] Open
Abstract
Yes-associated protein 1 (YAP1) interacts with TEAD transcription factor in the nucleus and upregulates TEAD-target genes. YAP1 is phosphorylated by large tumor suppressor (LATS) kinases, the core kinases of the Hippo pathway, at 5 serine residues and is sequestered and degraded in the cytoplasm. In human cancers with the dysfunction of the Hippo pathway, YAP1 becomes hyperactive and confers malignant properties to cancer cells. We have observed that cold shock induces protein kinase C (PKC)-mediated phosphorylation of YAP1. PKC phosphorylates YAP1 at 3 serine residues among LATS-mediate phosphorylation sites. Importantly, PKC activation recruits YAP1 to the cytoplasm even in LATS-depleted cancer cells and reduces the cooperation with TEAD. PKC activation induces promyelocytic leukemia protein-mediated SUMOylation of YAP1. SUMOylated YAP1 remains in the nucleus, binds to p73, and promotes p73-target gene transcription. Bryostatin, a natural anti-neoplastic reagent that activates PKC, induces YAP1/p73-mediated apoptosis in cancer cells. Bryostatin reverses malignant transformation caused by the depletion of LATS kinases. Therefore, bryostatin and other reagents that activate PKC are expected to control cancers with the dysfunction of the Hippo pathway.
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Affiliation(s)
- Caleb Kwame Sinclear
- Department of Medical BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Junichi Maruyama
- Laboratory for Integrated Cellular SystemsRIKEN Center for Integrative Medical SciencesYokohamaJapan
| | - Shunta Nagashima
- Department of Medical BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Kyoko Arimoto‐Matsuzaki
- Department of Medical BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Joshua Agbemefa Kuleape
- Department of Medical BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Hiroaki Iwasa
- Department of Molecular BiologySchool of MedicineInternational University of Health and WelfareNaritaJapan
| | - Hiroshi Nishina
- Department of Developmental and Regenerative BiologyMedical Research InstituteTokyo Medical and Dental UniversityTokyoJapan
| | - Yutaka Hata
- Department of Medical BiochemistryGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan,Center for Brain Integration ResearchTokyo Medical and Dental UniversityTokyoJapan
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30
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MicroRNA-181a Regulates the Proliferation and Differentiation of Hu Sheep Skeletal Muscle Satellite Cells and Targets the YAP1 Gene. Genes (Basel) 2022; 13:genes13030520. [PMID: 35328074 PMCID: PMC8949050 DOI: 10.3390/genes13030520] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 02/05/2023] Open
Abstract
MicroRNA (miRNA) is of great importance to muscle growth and development, including the regulation of the proliferation and differentiation of skeletal muscle satellite cells (SMSCs). In our research group’s previous study, we found that miR-181a is differentially expressed in the longissimus dorsi muscle of Hu sheep at different stages. We speculated that miR-181a may participate in the growth and development process of Hu sheep. To understand the mechanism of miR-181a regulating the growth and development of Hu sheep skeletal muscle, we extracted skeletal muscle satellite cells from the longissimus dorsi muscle of 3-month-old Hu sheep fetuses and performed a series of experiments. Our results showed that miR-181a suppressed SMSCs’ proliferation using QRT-PCR, Western blot, CCK-8, EDU, and Flow cytometry cycle tests. In addition, QRT-PCR, Western blot, and immunofluorescence indicated that miR-181a facilitated the differentiation of SMSCs. Then, we used dual-luciferase reporter gene detection, QRT-PCR, and Western blot to find that the Yes1-related transcription regulator (YAP1) is the target gene of miR-181a. Our study supplies a research basis for understanding the regulation mechanism of miR-181a on the growth of Hu sheep skeletal muscle.
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Guo Y, Luo J, Zou H, Liu C, Deng L, Li P. Context-dependent transcriptional regulations of YAP/TAZ in cancer. Cancer Lett 2022; 527:164-173. [PMID: 34952145 DOI: 10.1016/j.canlet.2021.12.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/20/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023]
Abstract
As the downstream effectors of Hippo pathway, YAP/TAZ are identified to participate in organ growth, regeneration and tumorigenesis. However, owing to lack of a DNA-binding domain, YAP/TAZ usually act as coactivators and cooperate with other transcription factors or partners to mediate their transcriptional outputs. In this article, we first present an overview of the core components and the upstream regulators of Hippo-YAP/TAZ signaling in mammals, and then systematically summarize the identified transcription factors or partners that are responsible for the downstream transcriptional output of YAP/TAZ in various cancers.
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Affiliation(s)
- Yibo Guo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Juan Luo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Hailin Zou
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Chenxin Liu
- Key Laboratory for Green Chemical Process of Ministry of Education, Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Hubei Engineering Research Center for Advanced Fine Chemicals, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, Hubei, 430205, People's Republic of China
| | - Liang Deng
- Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Peng Li
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China.
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YAP ISGylation increases its stability and promotes its positive regulation on PPP by stimulating 6PGL transcription. Cell Death Dis 2022; 8:59. [PMID: 35149670 PMCID: PMC8837792 DOI: 10.1038/s41420-022-00842-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/20/2021] [Accepted: 01/20/2022] [Indexed: 11/24/2022]
Abstract
Yes-associated protein (YAP) activation is crucial for tumor formation and development, and its stability is regulated by ubiquitination. ISGylation is a type of ubiquitination like post-translational modification, whereas whether YAP is ISGylated and how ISGylation influences YAP ubiquitination-related function remains uncovered. In addition, YAP can activate glucose metabolism by activating the hexosamine biosynthesis pathway (HBP) and glycolysis, and generate a large number of intermediates to promote tumor proliferation. However, whether YAP stimulates the pentose phosphate pathway (PPP), another tumor-promoting glucose metabolism pathway, and the relationship between this stimulation and ISGylation needs further investigation. Here, we found that YAP was ISGylated and this ISGylation inhibited YAP ubiquitination, proteasome degradation, interaction with-beta-transducin repeat containing E3 ubiquitin-protein ligase (βTrCP) to promote YAP stability. However, ISGylation-induced pro-YAP effects were abolished by YAP K497R (K, lysine; R, arginine) mutation, suggesting K497 could be the major YAP ISGylation site. In addition, YAP ISGylation promoted cell viability, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor formation. YAP ISGylation also increased downstream genes transcription, including one of the key enzymes of PPP, 6-phosphogluconolactonase (6PGL). Mechanistically, YAP promoted 6PGL transcription by simultaneously recruiting SMAD family member 2 (SMAD2) and TEA domain transcription factor 4 (TEAD4) binding to the 6PGL promoter to activate PPP. In clinical lung adenocarcinoma (LUAD) specimens, we found that YAP ISGylation degree was positively associated with 6PGL mRNA level, especially in high glucose LUAD tissues compared to low glucose LUAD tissues. Collectively, this study suggested that YAP ISGylation is critical for maintaining its stability and further activation of PPP. Targeting ISGylated YAP might be a new choice for hyperglycemia cancer treatment.
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Luo J, Li P. Context-dependent transcriptional regulations of YAP/TAZ in stem cell and differentiation. Stem Cell Res Ther 2022; 13:10. [PMID: 35012640 PMCID: PMC8751096 DOI: 10.1186/s13287-021-02686-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023] Open
Abstract
Hippo pathway is initially identified as a master regulator for cell proliferation and organ size control, and the subsequent researches show this pathway is also involved in development, tissue regeneration and homeostasis, inflammation, immunity and cancer. YAP/TAZ, the downstream effectors of Hippo pathway, usually act as coactivators and are dependent on other transcription factors to mediate their transcriptional outputs. In this review, we will first provide an overview on the core components and regulations of Hippo pathway in mammals, and then systematically summarize the identified transcriptional factors or partners that are responsible for the transcriptional output of YAP/TAZ in stem cell and differentiation. More than that, we will discuss the potential applications and future directions based on these findings.
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Affiliation(s)
- Juan Luo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Peng Li
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, People's Republic of China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China.
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Noorbakhsh N, Hayatmoghadam B, Jamali M, Golmohammadi M, Kavianpour M. The Hippo signaling pathway in leukemia: function, interaction, and carcinogenesis. Cancer Cell Int 2021; 21:705. [PMID: 34953494 PMCID: PMC8710012 DOI: 10.1186/s12935-021-02408-7] [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: 08/24/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Cancer can be considered as a communication disease between and within cells; nevertheless, there is no effective therapy for the condition, and this disease is typically identified at its late stage. Chemotherapy, radiation, and molecular-targeted treatment are typically ineffective against cancer cells. A better grasp of the processes of carcinogenesis, aggressiveness, metastasis, treatment resistance, detection of the illness at an earlier stage, and obtaining a better therapeutic response will be made possible. Researchers have discovered that cancerous mutations mainly affect signaling pathways. The Hippo pathway, as one of the main signaling pathways of a cell, has a unique ability to cause cancer. In order to treat cancer, a complete understanding of the Hippo signaling system will be required. On the other hand, interaction with other pathways like Wnt, TGF-β, AMPK, Notch, JNK, mTOR, and Ras/MAP kinase pathways can contribute to carcinogenesis. Phosphorylation of oncogene YAP and TAZ could lead to leukemogenesis, which this process could be regulated via other signaling pathways. This review article aimed to shed light on how the Hippo pathway interacts with other cellular signaling networks and its functions in leukemia.
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Affiliation(s)
| | - Bentolhoda Hayatmoghadam
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Jamali
- Gene Therapy Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Golmohammadi
- Applied Cell Sciences and Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maria Kavianpour
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Xiao Y, Dong J. The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective. Cancers (Basel) 2021; 13:cancers13246214. [PMID: 34944834 PMCID: PMC8699626 DOI: 10.3390/cancers13246214] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 01/25/2023] Open
Abstract
Simple Summary Cancer is increasingly viewed as a cell cycle disease in that the dysregulation of the cell cycle machinery is a common feature in cancer. The Hippo signaling pathway consists of a core kinase cascade as well as extended regulators, which together control organ size and tissue homeostasis. The aberrant expression of cell cycle regulators and/or Hippo pathway components contributes to cancer development, and for this reason, we specifically focus on delineating the roles of the Hippo pathway in the cell cycle. Improving our understanding of the Hippo pathway from a cell cycle perspective could be used as a powerful weapon in the cancer battlefield. Abstract Cell cycle progression is an elaborate process that requires stringent control for normal cellular function. Defects in cell cycle control, however, contribute to genomic instability and have become a characteristic phenomenon in cancers. Over the years, advancement in the understanding of disrupted cell cycle regulation in tumors has led to the development of powerful anti-cancer drugs. Therefore, an in-depth exploration of cell cycle dysregulation in cancers could provide therapeutic avenues for cancer treatment. The Hippo pathway is an evolutionarily conserved regulator network that controls organ size, and its dysregulation is implicated in various types of cancers. Although the role of the Hippo pathway in oncogenesis has been widely investigated, its role in cell cycle regulation has not been comprehensively scrutinized. Here, we specifically focus on delineating the involvement of the Hippo pathway in cell cycle regulation. To that end, we first compare the structural as well as functional conservation of the core Hippo pathway in yeasts, flies, and mammals. Then, we detail the multi-faceted aspects in which the core components of the mammalian Hippo pathway and their regulators affect the cell cycle, particularly with regard to the regulation of E2F activity, the G1 tetraploidy checkpoint, DNA synthesis, DNA damage checkpoint, centrosome dynamics, and mitosis. Finally, we briefly discuss how a collective understanding of cell cycle regulation and the Hippo pathway could be weaponized in combating cancer.
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Affiliation(s)
| | - Jixin Dong
- Correspondence: ; Tel.: +402-559-5596; Fax: +402-559-4651
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Noor H, Briggs NE, McDonald KL, Holst J, Vittorio O. TP53 Mutation Is a Prognostic Factor in Lower Grade Glioma and May Influence Chemotherapy Efficacy. Cancers (Basel) 2021; 13:5362. [PMID: 34771529 PMCID: PMC8582451 DOI: 10.3390/cancers13215362] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/17/2021] [Accepted: 10/22/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Identification of prognostic biomarkers in cancers is a crucial step to improve overall survival (OS). Although mutations in tumour protein 53 (TP53) is prevalent in astrocytoma, the prognostic effects of TP53 mutation are unclear. METHODS In this retrospective study, we sequenced TP53 exons 1 to 10 in a cohort of 102 lower-grade glioma (LGG) subtypes and determined the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. Publicly available datasets were analysed to confirm the findings. RESULTS In astrocytoma, mutations in TP53 codon 273 were associated with a significantly increased OS compared to the TP53 wild-type (HR (95% CI): 0.169 (0.036-0.766), p = 0.021). Public datasets confirmed these findings. TP53 codon 273 mutant astrocytomas were significantly more chemosensitive than TP53 wild-type astrocytomas (HR (95% CI): 0.344 (0.13-0.88), p = 0.0148). Post-chemotherapy, a significant correlation between TP53 and YAP1 mRNA was found (p = 0.01). In O (6)-methylguanine methyltransferase (MGMT) unmethylated chemotherapy-treated astrocytoma, both TP53 codon 273 and YAP1 mRNA were significant prognostic markers. In oligodendroglioma, TP53 mutations were associated with significantly decreased OS. CONCLUSIONS Based on these findings, we propose that certain TP53 mutant astrocytomas are chemosensitive through the involvement of YAP1, and we outline a potential mechanism. Thus, TP53 mutations may be key drivers of astrocytoma therapeutic efficacy and influence survival outcomes.
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Affiliation(s)
- Humaira Noor
- Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2031, Australia;
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW 2031, Australia;
| | - Nancy E. Briggs
- Stats Central, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW 2031, Australia;
| | - Kerrie L. McDonald
- Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2031, Australia;
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW 2031, Australia;
| | - Jeff Holst
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW 2031, Australia;
- Translational Cancer Metabolism Laboratory, School of Medical Sciences, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2031, Australia
| | - Orazio Vittorio
- School of Women’s & Children’s Health, UNSW Medicine, University of NSW, Randwick, NSW 2031, Australia;
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW 2031, Australia
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Riluzole-induced apoptosis in osteosarcoma is mediated through Yes-associated protein upon phosphorylation by c-Abl Kinase. Sci Rep 2021; 11:20974. [PMID: 34697383 PMCID: PMC8546089 DOI: 10.1038/s41598-021-00439-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 10/12/2021] [Indexed: 12/17/2022] Open
Abstract
Our lab has previously demonstrated Riluzole to be an effective drug in inhibiting proliferation and inducing apoptosis in both human and mouse osteosarcoma. Yes-associated protein is a transcription co-activator, known to be involved in cell proliferation or apoptosis depending on its protein partner. In the present study we investigated the role of YAP in apoptosis in osteosarcoma, we hypothesized that YAP may be activated by Riluzole to induce apoptosis in osteosarcoma. By knocking down the expression of YAP, we have demonstrated that Riluzole failed to induce apoptosis in YAP deficient osteosarcoma cells. Riluzole caused translocation of YAP from the cytoplasm to the nucleus, indicating YAP’s role in apoptosis. Both Riluzole-induced phosphorylation of YAP at tyrosine 357 and Riluzole-induced apoptosis were blocked by inhibitors of c-Abl kinase. In addition, knockdown of c-Abl kinase prevented Riluzole-induced apoptosis in LM7 cells. We further demonstrated that Riluzole promoted interaction between YAP and p73, while c-Abl kinase inhibitors abolished the interaction. Subsequently, we demonstrated that Riluzole enhanced activity of the Bax promoter in a luciferase reporter assay and enhanced YAP/p73 binding on endogenous Bax promoter in a ChIP assay. Our data supports a novel mechanism in which Riluzole activates c-Abl kinase to regulate pro-apoptotic activity of YAP in osteosarcoma.
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38
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Xu S, Liu Y, Hu R, Wang M, Stöhr O, Xiong Y, Chen L, Kang H, Zheng L, Cai S, He L, Wang C, Copps KD, White MF, Miao J. TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states. eLife 2021; 10:e57462. [PMID: 34622775 PMCID: PMC8555985 DOI: 10.7554/elife.57462] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 08/13/2021] [Indexed: 12/11/2022] Open
Abstract
The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiological and pathological states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ is abundantly expressed in pericentral hepatocytes and its expression is markedly reduced by fasting. TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to the GR response element in gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate that hepatic TAZ inhibits GR transactivation of gluconeogenic genes and coordinates gluconeogenesis in response to physiological fasting and feeding.
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Affiliation(s)
- Simiao Xu
- Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Branch of the National Clinical Research Center for Metabolic DiseaseWuhanChina
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
| | - Yangyang Liu
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Ruixiang Hu
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Min Wang
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Department of Pathology, Beth Israel Deaconess Medical CenterBostonUnited States
| | - Oliver Stöhr
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
| | - Yibo Xiong
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
| | - Liang Chen
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
- College of Science, Northeastern UniversityBostonUnited States
| | - Hong Kang
- Department of Systemic Biology, Harvard Medical SchoolBostonUnited States
| | - Lingyun Zheng
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
| | - Songjie Cai
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
- Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolBostonUnited States
| | - Li He
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
| | - Cunchuan Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Kyle D Copps
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
| | - Morris F White
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
| | - Ji Miao
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical SchoolBostonUnited States
- Department of Pediatrics, Harvard Medical SchoolBostonUnited States
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Mei L, Qv M, Bao H, He Q, Xu Y, Zhang Q, Shi W, Ren Q, Yan Z, Xu C, Tang C, Hussain M, Zeng LH, Wu X. SUMOylation activates large tumour suppressor 1 to maintain the tissue homeostasis during Hippo signalling. Oncogene 2021; 40:5357-5366. [PMID: 34267330 DOI: 10.1038/s41388-021-01937-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 06/23/2021] [Accepted: 07/01/2021] [Indexed: 02/07/2023]
Abstract
Large tumour suppressor (LATS) 1/2, the core kinases of Hippo signalling, are critical for maintaining tissue homeostasis. Here, we investigate the role of SUMOylation in the regulation of LATS activation. High cell density induces the expression of components of the SUMOylation machinery and enhances the SUMOylation and activation of Lats1 but not Lats2, whereas genetic deletion of the SUMOylation E2 ligase, Ubc9, abolishes this Lats1 activation. Moreover, SUMOylation occurs at the K830 (mouse K829) residue to activate LATS1 and depends on the PIAS1/2 E3 ligase. Whereas the K830 deSUMOylation mutation of LATS1 found in the human metastatic prostate cancers eliminates the kinase activity by attenuating the formation of the phospho-MOB1/phospho-LATS1 complex. As a result, the LATS1(K830R) transgene phenocopies Yap transgene to cause the oversized livers in mice, whereas Lats1(K829R) knock-in phenocopies the deletion of Lats1 in causing the reproductive and endocrine defects and ovary tumours in mice. Thus, SUMOylation-mediated LATS1 activation is an integral component of Hippo signalling in the regulation of tissues homeostasis.
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Affiliation(s)
- Liu Mei
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Biochemistry and Biophysics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA
| | - Meiyu Qv
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hangyang Bao
- Department of Physiology, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiangqiang He
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Yana Xu
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qin Zhang
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Shi
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Biology and Genetics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA
| | - Qianlei Ren
- Department of Pharmacology, Zhejiang University City College, Hangzhou, China
| | - Ziyi Yan
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengyun Xu
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Tang
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Musaddique Hussain
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ling-Hui Zeng
- Department of Pharmacology, Zhejiang University City College, Hangzhou, China.
| | - Ximei Wu
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Lopez-Hernandez A, Sberna S, Campaner S. Emerging Principles in the Transcriptional Control by YAP and TAZ. Cancers (Basel) 2021; 13:cancers13164242. [PMID: 34439395 PMCID: PMC8391352 DOI: 10.3390/cancers13164242] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/13/2021] [Accepted: 08/15/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary YAP and TAZ are transcriptional cofactors that integrate several upstream signals to generate context-dependent transcriptional responses. This requires extensive integration with epigenetic regulators and other transcription factors. The molecular and genomic characterization of YAP and TAZ nuclear function has broad implications both in physiological and pathological settings. Abstract Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we will revise the current literature and provide an overview of how YAP/TAZ control transcription. We will focus on data concerning the modulation of the basal transcriptional machinery, their ability to epigenetically remodel the enhancer–promoter landscape, and the mechanisms used to integrate transcriptional cues from multiple pathways. This reveals how YAP/TAZ activation in cancer cells leads to extensive transcriptional control that spans several hallmarks of cancer. The definition of the molecular mechanism of transcriptional control and the identification of the pathways regulated by YAP/TAZ may provide therapeutic opportunities for the effective treatment of YAP/TAZ-driven tumors.
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41
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Wrestling and Wrapping: A Perspective on SUMO Proteins in Schwann Cells. Biomolecules 2021; 11:biom11071055. [PMID: 34356679 PMCID: PMC8301837 DOI: 10.3390/biom11071055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 11/20/2022] Open
Abstract
Schwann cell development and peripheral nerve myelination are finely orchestrated multistep processes; some of the underlying mechanisms are well described and others remain unknown. Many posttranslational modifications (PTMs) like phosphorylation and ubiquitination have been reported to play a role during the normal development of the peripheral nervous system (PNS) and in demyelinating neuropathies. However, a relatively novel PTM, SUMOylation, has not been studied in these contexts. SUMOylation involves the covalent attachment of one or more small ubiquitin-like modifier (SUMO) proteins to a substrate, which affects the function, cellular localization, and further PTMs of the conjugated protein. SUMOylation also regulates other proteins indirectly by facilitating non-covalent protein–protein interaction via SUMO interaction motifs (SIM). This pathway has important consequences on diverse cellular processes, and dysregulation of this pathway has been reported in several diseases including neurological and degenerative conditions. In this article, we revise the scarce literature on SUMOylation in Schwann cells and the PNS, we propose putative substrate proteins, and we speculate on potential mechanisms underlying the possible involvement of this PTM in peripheral myelination and neuropathies.
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42
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Wu B, Tang X, Ke H, Zhou Q, Zhou Z, Tang S, Ke R. Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study. Pathol Oncol Res 2021; 27:1609768. [PMID: 34257617 PMCID: PMC8262238 DOI: 10.3389/pore.2021.1609768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/24/2021] [Indexed: 12/20/2022]
Abstract
Background: Yes-associated protein 1 (YAP1) is the main downstream effector of the Hippo signaling pathway, which is involved in tumorigenesis. This study aimed to comprehensively understand the prognostic performances of YAP1 expression and its potential mechanism in pan-cancers by mining databases. Methods: The YAP1 expression was evaluated by the Oncomine database and GEPIA tool. The clinical significance of YAP1 expression was analyzed by the UALCAN, GEPIA, and DriverDBv3 database. Then, the co-expressed genes with YAP1 were screened by the LinkedOmics, and annotated by the Metascape and DAVID database. Additionally, by the MitoMiner 4.0 v tool, the YAP1 co-expressed genes were screened to obtain the YAP1-associated mitochondrial genes that were further enriched by DAVID and analyzed by MCODE for the hub genes. Results: YAP1 was differentially expressed in human cancers. Higher YAP1 expression was significantly associated with poorer overall survival and disease-free survival in adrenocortical carcinoma (ACC), brain Lower Grade Glioma (LGG), and pancreatic adenocarcinoma (PAAD). The LinkedOmics analysis revealed 923 co-expressed genes with YAP1 in adrenocortical carcinoma, LGG and PAAD. The 923 genes mainly participated in mitochondrial functions including mitochondrial gene expression and mitochondrial respiratory chain complex I assembly. Of the 923 genes, 112 mitochondrial genes were identified by MitoMiner 4.0 v and significantly enriched in oxidative phosphorylation. The MCODE analysis identified three hub genes including CHCHD1, IDH3G and NDUFAF5. Conclusion: Our findings showed that the YAP1 overexpression could be a biomarker for poor prognosis in ACC, LGG and PAAD. Specifically, the YAP1 co-expression genes were mainly involved in the regulation of mitochondrial function especially in oxidative phosphorylation. Thus, our findings provided evidence of the carcinogenesis of YAP1 in human cancers and new insights into the mechanisms underlying the role of YAP1 in mitochondrial dysregulation.
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Affiliation(s)
- Baojin Wu
- Department of Plastic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinjie Tang
- Department of Plastic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Honglin Ke
- Department of Emergency, Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Qiong Zhou
- Department of Statistics, Florida State University, Tallahassee, FL, United States
| | - Zhaoping Zhou
- Department of Plastic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Shao Tang
- Department of Statistics, Florida State University, Tallahassee, FL, United States
| | - Ronghu Ke
- Department of Plastic Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Imai S, Ooki T, Murata-Kamiya N, Komura D, Tahmina K, Wu W, Takahashi-Kanemitsu A, Knight CT, Kunita A, Suzuki N, Del Valle AA, Tsuboi M, Hata M, Hayakawa Y, Ohnishi N, Ueda K, Fukayama M, Ushiku T, Ishikawa S, Hatakeyama M. Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis. Cell Host Microbe 2021; 29:941-958.e10. [PMID: 33989515 DOI: 10.1016/j.chom.2021.04.006] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/17/2021] [Accepted: 04/14/2021] [Indexed: 12/15/2022]
Abstract
Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. It hereby induces BRCAness that promotes DNA double-strand breaks (DSBs) while disabling error-free homologous recombination-mediated DNA repair. The CagA/PAR1b interaction also stimulates Hippo signaling that circumvents apoptosis of DNA-damaged cells, giving cells time to repair DSBs through error-prone mechanisms. The DSB-activated p53-p21Cip1 axis inhibits proliferation of CagA-delivered cells, but the inhibition can be overcome by p53 inactivation. Indeed, sequential pulses of CagA in TP53-mutant cells drove somatic mutation with BRCAness-associated genetic signatures. Expansion of CagA-delivered cells with BRCAness-mediated genome instability, from which CagA-independent cancer-predisposing cells arise, provides a plausible "hit-and-run mechanism" of H. pylori CagA for gastric carcinogenesis.
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Affiliation(s)
- Satoshi Imai
- Department of Microbiology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Takuya Ooki
- Department of Microbiology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Naoko Murata-Kamiya
- Department of Microbiology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.
| | - Daisuke Komura
- Department of Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Kamrunnesa Tahmina
- Department of Microbiology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Weida Wu
- Department of Microbiology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | | | - Christopher Takaya Knight
- Department of Microbiology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Akiko Kunita
- Department of Pathology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Nobumi Suzuki
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Adriana A Del Valle
- Department of Microbiology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Mayo Tsuboi
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Masahiro Hata
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Naomi Ohnishi
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Koji Ueda
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Shumpei Ishikawa
- Department of Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan
| | - Masanori Hatakeyama
- Department of Microbiology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.
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Wu G, Hao C, Qi X, Nie J. Effect of Yes Associated Protein 1 Silence on Proliferation and Apoptosis of Bladder Cancer Cells. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Yes Associated Protein 1 (YAP) can act as either an oncoprotein or a tumor suppressor in different cellular contexts. However, the reports about the direct role of YAP silence in bladder cancer cells are rare. We designed loss-off-function experiments to investigate the effect of YAP
knockdown on bladder cancer cell proliferation, cell cycle and cell apoptosis. We examined YAP expression in human bladder cancer and paracancerous tissues using RT-qPCR, western blot and immunohisto-chemistry. YAP short hairpin RNA (shRNA) was successfully constructed and transfected into
T24 cells to knockdown YAP. Cell proliferation, cell cycle and cell apoptosis were analyzed by CCK-8 and flow cytometry. We found the expression levels of YAP mRNA and protein were significantly increased in the bladder cancer tissues when compared with that in the paracancerous tissues. shRNA
YAP inhibited cell proliferation, induced cell cycle arrest at G1 phase, and induced cell apoptosis. In conclusion, our findings provided the first evidence that YAP knockdown could inhibit cell proliferation and induce cell apoptosis of bladder cancer cells. YAP inhibition may be beneficial
in the treatment of bladder cancer.
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Affiliation(s)
- Gaoliang Wu
- Department of Urology, Jiangxi Cancer, Hospital, Nanchang 330029, Jiangxi, P. R. China
| | - Chao Hao
- Department of Urology, Jiangxi Cancer, Hospital, Nanchang 330029, Jiangxi, P. R. China
| | - Xueliang Qi
- Department of Urology, Jiangxi Cancer, Hospital, Nanchang 330029, Jiangxi, P. R. China
| | - Jianqiang Nie
- Department of Urology, Jiangxi Cancer, Hospital, Nanchang 330029, Jiangxi, P. R. China
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45
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Li Y, Sun C, Tan Y, Zhang H, Li Y, Zou H. ITGB1 enhances the Radioresistance of human Non-small Cell Lung Cancer Cells by modulating the DNA damage response and YAP1-induced Epithelial-mesenchymal Transition. Int J Biol Sci 2021; 17:635-650. [PMID: 33613118 PMCID: PMC7893583 DOI: 10.7150/ijbs.52319] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/27/2020] [Indexed: 12/13/2022] Open
Abstract
Objectives: Radiotherapy has played a limited role in the treatment of non-small cell lung cancer (NSCLC) due to the risk of tumour radioresistance. We previously established the radioresistant non-small cell lung cancer (NSCLC) cell line H460R. In this study, we identified differentially expressed genes between these radioresistant H460R cells and their radiosensitive parent line. We further evaluated the role of a differentially expressed gene, ITGB1, in NSCLC cell radioresistance and as a potential target for improving radiosensitivity. Materials and Methods: The radiosensitivity of NSCLC cells was evaluated by flow cytometry, colony formation assays, immunofluorescence, and Western blotting. Bioinformatics assay was used to identify the effect of ITGB1 and YAP1 expression in NSCLC tissues. Results: ITGB1 mRNA and protein expression levels were higher in H460R than in the parental H460 cells. We observed lower clonogenic survival and cell viability and a higher rate of apoptosis of ITGB1-knockdown A549 and H460R cells than of wild type cells post-irradiation. Transfection with an ITGB1 short hairpin (sh) RNA enhanced radiation-induced DNA damage and G2/M phase arrest. Moreover, ITGB1 induced epithelial-mesenchymal transition (EMT) of NSCLC cells. Silencing ITGB1 suppressed the expression and intracellular translocation of Yes-associated protein 1 (YAP1), a downstream effector of ITGB1. Conclusions: ITGB1 may induce radioresistance via affecting DNA repair and YAP1-induced EMT. Taken together, our data suggest that ITGB1 is an attractive therapeutic target to overcome NSCLC cell radioresistance.
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Affiliation(s)
- Yuexian Li
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
| | - Cheng Sun
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
| | - Yonggang Tan
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
| | - Heying Zhang
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
| | - Yuchao Li
- School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases
| | - Huawei Zou
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
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46
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Zhou W, Liu M, Li X, Zhang P, Li J, Zhao Y, Sun G, Mao W. Arsenic nano complex induced degradation of YAP sensitized ESCC cancer cells to radiation and chemotherapy. Cell Biosci 2020; 10:146. [PMID: 33353561 PMCID: PMC7756940 DOI: 10.1186/s13578-020-00508-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/27/2020] [Indexed: 02/01/2023] Open
Abstract
Background Increased reactive oxygen species (ROS) production by arsenic treatment in solid tumors showed to be effective to sensitize cancer cells to chemotherapies. Arsenic nano compounds are known to increase the ROS production in solid tumors. Methods In this study we developed arsenic–ferrosoferric oxide conjugated Nano Complex (As2S2–Fe3O4, AFCNC) to further promote the ROS induction ability of arsenic reagent in solid tumors. We screen for the molecular pathways that are affect by arsenic treatment in ESCC cancer cells. And explored the underlying molecular mechanism for the arsenic mediated degradations of the key transcription factor we identified in the gene microarray screen. Mouse xenograft model were used to further verify the synthetic effects of AFCNC with chemo and radiation therapies, and the molecular target of arsenic treatment is verified with IHC analysis. Results With gene expression microarray analysis we found Hippo signaling pathway is specifically affected by arsenic treatment, and induced ubiquitination mediated degradation of YAP in KYSE-450 esophageal squamous cell carcinoma (ESCC) cells. Mechanistically we proved PML physically interacted with YAP, and arsenic induced degradation PML mediated the degradation of YAP in ESCC cells. As a cancer stem cell related transcription factor, YAP 5SA over expressions in cancer cells are correlated with resistance to chemo and radiation therapies. We found AFCNC treatment inhibited the increased invasion and migration ability of YAP 5SA overexpressing KYSE-450 cells. AFCNC treatment also effectively reversed protective effects of YAP 5SA overexpression against cisplatin induced apoptosis in KYSE-450 cells. Lastly, with ESCC mouse xenograft model we found AFCNC combined with cisplatin treatment or radiation therapy significantly reduced the tumor volumes in vivo in the xenograft ESCC tumors. Conclusions Together, these findings suggested besides ROS, YAP is a potential target for arsenic based therapy in ESCC, which should play an important role in the synthetic effects of arsenic nano complex with chemo and radiation therapy.
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Affiliation(s)
- Wei Zhou
- Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine of Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Meiyue Liu
- School of Public Health, North China University of Science and Technology Affiliated People's Hospital, North China University of Science and Technology, Tangshan, 063001, China
| | - Xia Li
- Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine of Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Peng Zhang
- Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine of Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Jiong Li
- Department of Medicinal Chemistry, Massey Cancer Center, Philips Institute for Oral Health Research , Virginia Commonwealth University, Richmond, VA, 23298-0540, USA
| | - Yue Zhao
- Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine of Chinese Academy of Sciences, Hangzhou, 310022, China.
| | - Guogui Sun
- School of Public Health, North China University of Science and Technology Affiliated People's Hospital, North China University of Science and Technology, Tangshan, 063001, China.
| | - Weimin Mao
- Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine of Chinese Academy of Sciences, Hangzhou, 310022, China.
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47
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Wang D, He J, Huang B, Liu S, Zhu H, Xu T. Emerging role of the Hippo pathway in autophagy. Cell Death Dis 2020; 11:880. [PMID: 33082313 PMCID: PMC7576599 DOI: 10.1038/s41419-020-03069-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/07/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023]
Abstract
Autophagy is a dynamic circulatory system that occurs in all eukaryotic cells. Cytoplasmic material is transported to lysosomes for degradation and recovery through autophagy. This provides energy and macromolecular precursors for cell renewal and homeostasis. The Hippo-YAP pathway has significant biological properties in controlling organ size, tissue homeostasis, and regeneration. Recently, the Hippo-YAP axis has been extensively referred to as the pathophysiological processes regulating autophagy. Understanding the cellular and molecular basis of these processes is crucial for identifying disease pathogenesis and novel therapeutic targets. Here we review recent findings from Drosophila models to organisms. We particularly emphasize the regulation between Hippo core components and autophagy, which is involved in normal cellular regulation and the pathogenesis of human diseases, and its application to disease treatment.
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Affiliation(s)
- Dongying Wang
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, 218 Zi Qiang Street, Changchun, Jilin, 130000, China
| | - Jiaxing He
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, 218 Zi Qiang Street, Changchun, Jilin, 130000, China
| | - Bingyu Huang
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, 218 Zi Qiang Street, Changchun, Jilin, 130000, China
| | - Shanshan Liu
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, 218 Zi Qiang Street, Changchun, Jilin, 130000, China
| | - Hongming Zhu
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, 218 Zi Qiang Street, Changchun, Jilin, 130000, China
| | - Tianmin Xu
- Department of Obstetrics and Gynecology, The Second Hospital, Jilin University, 218 Zi Qiang Street, Changchun, Jilin, 130000, China.
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48
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Reggiani F, Gobbi G, Ciarrocchi A, Sancisi V. YAP and TAZ Are Not Identical Twins. Trends Biochem Sci 2020; 46:154-168. [PMID: 32981815 DOI: 10.1016/j.tibs.2020.08.012] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 08/13/2020] [Accepted: 08/27/2020] [Indexed: 12/12/2022]
Abstract
Yes-associated protein (YAP) and TAZ (WW domain containing transcription regulator 1, or WWTR1) are paralog transcriptional regulators, able to integrate mechanical, metabolic, and signaling inputs to regulate cell growth and differentiation during development and neoplastic progression. YAP and TAZ hold common and distinctive structural features, reflecting only partially overlapping regulatory mechanisms. The two paralogs interact with both shared and specific transcriptional partners and control nonidentical transcriptional programs. Although most of the available literature considers YAP and TAZ as functionally redundant, they play distinctive or even contrasting roles in different contexts. The issue of their divergent roles is currently underexplored but holds fundamental implications for mechanistic and translational studies. Here, we aim to review the available literature on the biological functions of YAP and TAZ, highlighting differential roles that distinguish these two paralogues.
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Affiliation(s)
- Francesca Reggiani
- Laboratory of Translational Research, Azienda USL- IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Giulia Gobbi
- Laboratory of Translational Research, Azienda USL- IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda USL- IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Valentina Sancisi
- Laboratory of Translational Research, Azienda USL- IRCCS di Reggio Emilia, Reggio Emilia, Italy.
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49
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Fan H, Wang X, Li W, Shen M, Wei Y, Zheng H, Kang Y. ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP. Genes Dev 2020; 34:1359-1372. [PMID: 32943576 PMCID: PMC7528707 DOI: 10.1101/gad.339796.120] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/05/2020] [Indexed: 12/12/2022]
Abstract
In this study, Fan et al. studied the post-translational regulation of transcription factor SNAI2, which plays key roles during development and promotes metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. They performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation, thereby establishing ASB13 as a suppressor of breast cancer metastasis. Transcription factor SNAI2 plays key roles during development and has also been known to promote metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. However, the post-translational regulation of SNAI2 is less well studied. We performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation. ASB13 knockout in breast cancer cells promoted cell migration and decreased F-actin polymerization, while overexpression of ASB13 suppressed lung metastasis. Furthermore, ASB13 knockout decreased YAP expression, and such regulation is dependent on an increased protein level of SNAI2, which in turn represses YAP transcription. YAP suppresses tumor progression in breast cancer, as YAP knockout increases tumorsphere formation, anchorage-independent colony formation, cell migration in vitro, and lung metastasis in vivo. Clinical data analysis reveals that ASB13 expression is positively correlated with improved overall survival in breast cancer patients. These findings establish ASB13 as a suppressor of breast cancer metastasis by promoting degradation of SNAI2 and relieving its transcriptional repression of YAP.
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Affiliation(s)
- Huijuan Fan
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xuxiang Wang
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Wenyang Li
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Minhong Shen
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Yong Wei
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Hanqiu Zheng
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.,Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
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50
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Wu T, Wang S, Wang L, Zhang W, Chen W, Lv X, Li Y, Hussain Z, Sun W. Long Noncoding RNA (lncRNA) CTTN-IT1 Elevates Skeletal Muscle Satellite Cell Proliferation and Differentiation by Acting as ceRNA for YAP1 Through Absorbing miR-29a in Hu Sheep. Front Genet 2020; 11:843. [PMID: 32849826 PMCID: PMC7427492 DOI: 10.3389/fgene.2020.00843] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/13/2020] [Indexed: 12/26/2022] Open
Abstract
Characterizing the factors that regulate the growth and development of muscle is central to animal production. Skeletal muscle satellite cells (SMSCs) provide an important material for simulating the proliferation and differentiation of muscle cells. YAP1, which can promote muscle growth, is closely related to the proliferation of SMSCs in Hu sheep (Ovis aries). In addition, some miRNAs, such as miR-541-3p, miR-142-5p, and miR-29a, can play critical roles in muscle growth by specifically binding with their target mRNAs. Meanwhile, lncRNA can competitively bind these miRNAs and reduce the regulatory effect of miRNAs on their target genes and thus play critical roles themselves in muscle growth. However, the regulatory molecular mechanism of miRNA and lncRNA on SMSC proliferation through YAP1 remains unclear. Here, we characterized the regulatory network among YAP1 and its targeted miRNAs and lncRNAs in Hu sheep SMSCs. The potential ncRNAs that regulate YAP1 (miR-29a and CTTN-IT1) were predicted through multilevel bioinformatics analysis. Dual-luciferase assays, RT-qPCR, and western blots revealed that miR-29a can significantly reduce the mRNA and protein expression level by binding to a specific 3′-UTR of YAP1 (P < 0.05), while CTTN-IT1 can restore the expression of YAP1 through competitive binding to miR-29a. Furthermore, the mRNA and protein expression levels of MyoG, MyoD, and MyHC showed that miR-29a can inhibit the expression of genes related to the differentiation of SMSCs, and CTTN-IT1 can increase the expression of these same genes. Thus, miR-29a may inhibit the differentiation of SMSCs and CTTN-IT1 can restore this inhibition. The EdU staining assay indicated that excessive miR-29a can significantly reduce the proliferation ability of SMSCs (P < 0.05), while overexpression of CTTN-IT1 can significantly increase the proliferation of SMSCs (P < 0.01). CTTN-IT1 is a novel lncRNA that is a competing endogenous RNA (ceRNA) of miR-29a and can promote SMSC proliferation and differentiation by restoring the expression of YAP1 when it is inhibited by miR-29a in Hu sheep. Overall, our findings construct a CTTN-IT1-miR-29a-YAP1 regulatory network that will help contribute new insight into improving the muscle development of Hu sheep.
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Affiliation(s)
- Tianyi Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Shanhe Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Lihong Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Weibo Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Weihao Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Xiaoyang Lv
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Yue Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Zahid Hussain
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Wei Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, China.,Jiangsu Co-innovation Center for Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
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