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1
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Kim JK, Kim J, Kim H, Jin H, Yoo Y, Fei X, Maeng HJ, Seo SY, Han G, No KT. Structure-based optimization of TEAD inhibitors: Exploring a novel subpocket near Glu347 for the treatment of NF2-mutant cancer. Bioorg Chem 2025; 159:108425. [PMID: 40168885 DOI: 10.1016/j.bioorg.2025.108425] [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: 11/18/2024] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/03/2025]
Abstract
The Hippo signaling pathway is critical for regulating cell growth, tissue homeostasis, and organ size. Dysregulation of this pathway has been associated with a range of pathologies, especially cancer, through its modulation of downstream effectors-Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ). These proteins bind to transcriptional enhanced associate domain (TEAD) proteins and function as transcription factors in the nucleus, producing oncogenic target genes such as CTGF and CYR61. TEAD proteins require palmitoylation via a covalent bond with cysteine in the central pocket to bind YAP/TAZ. Therefore, competitive inhibition that prevents palmitoylation could serve as an effective anticancer strategy. In this study, we analyzed the crystal structures of the known inhibitor VT-105 bound to TEAD3 to identify new binding spots that were previously unexplored, with the aim of discovering more potent compounds using structure-based drug design. Consequently, we identified a novel hydrogen-bonding site and discovered C-2, which effectively binds to this site, as confirmed by X-ray crystallography. Furthermore, C-2 exhibited stable pharmacokinetic properties and demonstrated impressive efficacy in a mouse xenograft model.
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Affiliation(s)
- Jin Kwan Kim
- Baobab AiBIO Co., Ltd., Incheon 21983, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Jinhyuk Kim
- Baobab AiBIO Co., Ltd., Incheon 21983, Republic of Korea; Department of Integrative Biotechnology, Yonsei University, Incheon 21983, Republic of Korea
| | - Hadong Kim
- Baobab AiBIO Co., Ltd., Incheon 21983, Republic of Korea
| | - Haiyan Jin
- Bioinformatics and Molecular Design Research Center (BMDRC), Incheon 21983, Republic of Korea
| | - Youngki Yoo
- Baobab AiBIO Co., Ltd., Incheon 21983, Republic of Korea
| | - Xiang Fei
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Han-Joo Maeng
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Seung-Yong Seo
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
| | - Gyoonhee Han
- Department of Integrative Biotechnology, Yonsei University, Incheon 21983, Republic of Korea; Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.
| | - Kyoung Tai No
- Baobab AiBIO Co., Ltd., Incheon 21983, Republic of Korea; Institute of Convergence Science and Technology, Yonsei University, Incheon 21983, Republic of Korea.
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2
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Zhang C, Guo J. Cell cycle disorders in podocytes: an emerging and increasingly recognized phenomenon. Cell Death Discov 2025; 11:182. [PMID: 40246828 PMCID: PMC12006314 DOI: 10.1038/s41420-025-02486-w] [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: 02/04/2025] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 04/19/2025] Open
Abstract
Proteinuria is observed in various kidney diseases and is frequently associated with a compromised glomerular filtration barrier. Podocytes, as a crucial component of this barrier, play an essential role in preserving the kidney's normal filtration function. Podocytes are terminally differentiated cells that typically do not proliferate. However, certain harmful stimuli can trigger podocytes to re-enter the cell cycle. Due to its unique cytoskeletal structure, podocytes are unable to maintain the structure of the foot process and complete cell division at the same time, eventually form binucleated or multinucleated podocytes. Studies have found that podocytes re-entering the cell cycle are more susceptible to injury, and are prone to detachment from the basement membrane or apoptosis, which are accompanied by the widening of foot processes. This eventually leads to podocyte mitotic catastrophe and the development of proteinuria. Podocyte cell cycle disorders have previously been found mainly in focal segmental glomerulosclerosis and IgA nephropathy. In recent years, this phenomenon has been frequently identified in diabetic kidney disease and lupus nephritis. An expanding body of research has begun to investigate the mechanisms underlying podocyte cell cycle disorders, including cell cycle re-entry, cell cycle arrest, and mitotic catastrophe. This review consolidates the existing literature on podocyte cell cycle disorders in renal diseases and summarizes the molecules that trigger podocyte re-entry into the cell cycle, thereby providing new drug targets for mitigating podocyte damage. This is essential for alleviating podocyte injury, reducing proteinuria, and delaying the progression of kidney diseases.
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Affiliation(s)
- Chaojie Zhang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jia Guo
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan, China.
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
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3
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Lu Y, Yan Z, Sun J, Wang C, Xu L, Lyu X, Wang X, Lou J, Huang H, Meng L, Zhao Y. Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo. J Med Chem 2025; 68:5616-5640. [PMID: 39804031 DOI: 10.1021/acs.jmedchem.4c02884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
Genetic mutations in components of the Hippo pathway frequently lead to the aberrant activation of TEADs, which is often associated with cancer. Consequently, TEADs have been actively pursued as therapeutic targets for diseases driven by TEAD overactivation. In this study, we report two series of TEAD PROTACs based on CRBN binders and VHL binders. Both series yielded potent TEAD degraders, including 19 and 40 (H122), which induced TEAD1 degradation with DC50 < 10 nM. Mechanistic studies demonstrated that the degradation of TEAD1 induced by 40 relied on CRBN binding, TEAD1 binding, E3 ligase activity, and a functional proteasome. RNA-seq analyses indicated that 40 significantly downregulated the expression of Myc target genes, as highlighted by GSEA analysis. More importantly, 40 exhibited robust antitumor efficacy in the MSTO-211H mouse xenograft model. Collectively, our results suggest that TEAD PROTACs have therapeutic potential for the treatment of cancers associated with TEAD overactivation.
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Affiliation(s)
- Yuhang Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Ziqin Yan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
| | - Jiaqi Sun
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Chenxu Wang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lan Xu
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xilin Lyu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
| | - Xiancheng Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Jianfeng Lou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - He Huang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Linghua Meng
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Yujun Zhao
- Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia Province 750004, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
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4
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Melrose J. Glycosaminoglycans, Instructive Biomolecules That Regulate Cellular Activity and Synaptic Neuronal Control of Specific Tissue Functional Properties. Int J Mol Sci 2025; 26:2554. [PMID: 40141196 PMCID: PMC11942259 DOI: 10.3390/ijms26062554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/22/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025] Open
Abstract
Glycosaminoglycans (GAGs) are a diverse family of ancient biomolecules that evolved over millennia as key components in the glycocalyx that surrounds all cells. GAGs have molecular recognition and cell instructive properties when attached to cell surface and extracellular matrix (ECM) proteoglycans (PGs), which act as effector molecules that regulate cellular behavior. The perception of mechanical cues which arise from perturbations in the ECM microenvironment allow the cell to undertake appropriate biosynthetic responses to maintain ECM composition and tissue function. ECM PGs substituted with GAGs provide structural support to weight-bearing tissues and an ability to withstand shear forces in some tissue contexts. This review outlines the structural complexity of GAGs and the diverse functional properties they convey to cellular and ECM PGs. PGs have important roles in cartilaginous weight-bearing tissues and fibrocartilages subject to tension and high shear forces and also have important roles in vascular and neural tissues. Specific PGs have roles in synaptic stabilization and convey specificity and plasticity in the regulation of neurophysiological responses in the CNS/PNS that control tissue function. A better understanding of GAG instructional roles over cellular behavior may be insightful for the development of GAG-based biotherapeutics designed to treat tissue dysfunction in disease processes and in novel tissue repair strategies following trauma. GAGs have a significant level of sophistication over the control of cellular behavior in many tissue contexts, which needs to be fully deciphered in order to achieve a useful therapeutic product. GAG biotherapeutics offers exciting opportunities in the modern glycomics arena.
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Affiliation(s)
- James Melrose
- Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia;
- Raymond Purves Bone and Joint Research Laboratories, Kolling Institute of Medical Research, Northern Sydney Local Health District, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
- Sydney Medical School, Northern, University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
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Tang B, Du Y, Wang J. TAZ-hTrap: A Rationally Designed, Disulfide-Stapled Tead Helical Hairpin Trap to Selectively Capture Hippo Signaling Taz With Potent Antigynecological Tumor Activity. J Mol Recognit 2025; 38:e3111. [PMID: 39626959 DOI: 10.1002/jmr.3111] [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: 04/02/2024] [Revised: 10/28/2024] [Accepted: 11/18/2024] [Indexed: 02/01/2025]
Abstract
Transcriptional enhanced associate domain (Tead)-mediated Hippo signaling pathway regulates diverse physiological processes; its dysfunction has been implicated in an increasing number of human gynecological cancers. The transcriptional coactivator with PDZ-binding motif (Taz) binds to and then activates Tead through forming a three-helix bundle (THB) at their complex interface. The THB is defined by a double-helical hairpin from Tead and a single α-helix from Taz, serving as the key interaction hotspot between Tead and Taz. In the present study, the helical hairpin was derived from Tead protein to generate a hairpin segment, which is a 25-mer polypeptide consisting of a longer helical arm-1 and a shorter helical arm-2 as well as a flexible loop linker between them. Dynamics simulation and energetics characterization revealed that the hairpin peptide is intrinsically disordered when splitting from its protein context, thus incurring a large entropy penalty upon binding to Taz α-helix. A disulfide bridge was introduced across the two helical arms of hairpin peptide to obtain a strong binder termed TAZ-hTrap, which can maintain in a considerably structured, native-like conformation in unbound state, and the entropy penalty was minimized by disulfide stapling to effectively improve its affinity toward the α-helix. These computational findings can be further substantiated by circular dichroism and fluorescence polarization at molecular level, and viability assay also observed a potent cytotoxic effect on diverse human gynecological tumors at cellular level. In addition, we further demonstrated that the TAZ-hTrap has a good selectivity for its cognate Taz over other noncognate proteins that share a high conservation with the Taz α-helix.
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Affiliation(s)
- Bin Tang
- Department of Gynecology, Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
| | - Yu Du
- Department of Gynecology, Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
| | - Jun Wang
- Department of Gynecology, Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
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6
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Saadh MJ, Ahmed HH, Kareem RA, Bishoyi AK, Roopashree R, Shit D, Arya R, Sharma A, Khaitov K, Sameer HN, Yaseen A, Athab ZH, Adil M. Molecular mechanisms of Hippo pathway in tumorigenesis: therapeutic implications. Mol Biol Rep 2025; 52:267. [PMID: 40014178 DOI: 10.1007/s11033-025-10372-y] [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: 11/15/2024] [Accepted: 02/17/2025] [Indexed: 02/28/2025]
Abstract
The Hippo signaling pathway is a pivotal regulator of tissue homeostasis, organ size, and cell proliferation. Its dysregulation is profoundly implicated in various forms of cancer, making it a highly promising target for therapeutic intervention. This review extensively evaluates the mechanisms underlying the dysregulation of the Hippo pathway in cancer cells and the molecular processes linking these alterations to tumorigenesis. Under normal physiological conditions, the Hippo pathway is a guardian, ensuring controlled cellular proliferation and programmed cell death. However, numerous mutations and epigenetic modifications can disrupt this equilibrium in cancer cells, leading to unchecked cell proliferation, enhanced survival, and metastatic capabilities. The pathway's interaction with other critical signaling networks, including Wnt/β-catenin, PI3K/Akt, TGF-β/SMAD, and EGFR pathways, further amplifies its oncogenic potential. Central to these disruptions is the activation of YAP and TAZ transcriptional coactivators, which drive the expression of genes that promote oncogenesis. This review delves into the molecular mechanisms responsible for the dysregulation of the Hippo pathway in cancer, elucidating how these disruptions contribute to tumorigenesis. We also explore potential therapeutic strategies, including inhibitors targeting YAP/TAZ activity and modulators of upstream signaling components. Despite significant advancements in understanding the Hippo pathway's role in cancer, numerous questions remain unresolved. Continued research is imperative to unravel the complex interactions within this pathway and to develop innovative and effective therapies for clinical application. In conclusion, the comprehensive understanding of the Hippo pathway's regulatory mechanisms offers significant potential for advancing cancer therapies, regenerative medicine, and treatments for chronic diseases. The translation of these insights into clinical practice will necessitate collaborative efforts from researchers, clinicians, and pharmaceutical developers to bring novel and effective therapies to patients, ultimately improving clinical outcomes and advancing the field of oncology.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | | | - Ashok Kumar Bishoyi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, 360003, India
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Debasish Shit
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
| | - Renu Arya
- Department of Pharmacy, Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - Abhishek Sharma
- Department of Medicine, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Kakhramon Khaitov
- Department of Dermatovenerology, Pediatric Dermatovenerology and AIDS, Tashkent Pediatric Medical Institute, Bogishamol Street 223, Tashkent, 100140, Uzbekistan
| | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Mohaned Adil
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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7
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Jiang H, Zhang C, Lin M, Yin Y, Deng S, Liu W, Zhuo B, Tian G, Du Y, Meng Z. Deciphering the mechanistic impact of acupuncture on the neurovascular unit in acute ischemic stroke: Insights from basic research in a narrative review. Ageing Res Rev 2024; 101:102536. [PMID: 39384155 DOI: 10.1016/j.arr.2024.102536] [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: 08/18/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/11/2024]
Abstract
Ischemic stroke(IS), a severe acute cerebrovascular disease, not only imposes a heavy economic burden on society but also presents numerous challenges in treatment. During the acute phase, while thrombolysis and thrombectomy serve as primary treatments, these approaches are restricted by a narrow therapeutic window. During rehabilitation, commonly used neuroprotective agents struggle with their low drug delivery efficiency and inadequate preclinical testing, and the long-term pharmacological and toxicity effects of nanomedicines remain undefined. Meanwhile, acupuncture as a therapeutic approach is widely acknowledged for its effectiveness in treating IS and has been recommended by the World Health Organization (WHO) as an alternative and complementary therapy, even though its exact mechanisms remain unclear. This review aims to summarize the known mechanisms of acupuncture and electroacupuncture (EA) in the treatment of IS. Research shows that acupuncture treatment mainly protects the neurovascular unit through five mechanisms: 1) reducing neuronal apoptosis and promoting neuronal repair and proliferation; 2) maintaining the integrity of the blood-brain barrier (BBB); 3) inhibiting the overactivation and polarization imbalance of microglia; 4) regulating the movement of vascular smooth muscle (VSM) cells; 5) promoting the proliferation of oligodendrocyte precursors. Through an in-depth analysis, this review reveals the multi-level, multi-dimensional impact of acupuncture treatment on the neurovascular unit (NVU) following IS, providing stronger evidence and a theoretical basis for its clinical application.
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Affiliation(s)
- Hailun Jiang
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Chao Zhang
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Mengxuan Lin
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Yu Yin
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shizhe Deng
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Wei Liu
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Bifang Zhuo
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Guang Tian
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Yuzheng Du
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
| | - Zhihong Meng
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
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8
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Li N, Liu YH, Wu J, Liu QG, Niu JB, Zhang Y, Fu XJ, Song J, Zhang SY. Strategies that regulate Hippo signaling pathway for novel anticancer therapeutics. Eur J Med Chem 2024; 276:116694. [PMID: 39047607 DOI: 10.1016/j.ejmech.2024.116694] [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: 05/22/2024] [Revised: 06/29/2024] [Accepted: 07/17/2024] [Indexed: 07/27/2024]
Abstract
As a highly conserved signaling network across different species, the Hippo pathway is involved in various biological processes. Dysregulation of the Hippo pathway could lead to a wide range of diseases, particularly cancers. Extensive researches have demonstrated the close association between dysregulated Hippo signaling and tumorigenesis as well as tumor progression. Consequently, targeting the Hippo pathway has emerged as a promising strategy for cancer treatment. In fact, there has been an increasing number of reports on small molecules that target the Hippo pathway, exhibiting therapeutic potential as anticancer agents. Importantly, some of Hippo signaling pathway inhibitors have been approved for the clinical trials. In this work, we try to provide an overview of the core components and signal transduction mechanisms of the Hippo signaling pathway. Furthermore, we also analyze the relationship between Hippo signaling pathway and cancers, as well as summarize the small molecules with proven anti-tumor effects in clinical trials or reported in literatures. Additionally, we discuss the anti-tumor potency and structure-activity relationship of the small molecule compounds, providing a valuable insight for further development of anticancer agents against this pathway.
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Affiliation(s)
- Na Li
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Yun-He Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Ji Wu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Qiu-Ge Liu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jin-Bo Niu
- The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yan Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiang-Jing Fu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention &Treatment, Zhengzhou, 450001, China.
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9
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Wang S, Shao D, Gao X, Zhao P, Kong F, Deng J, Yang L, Shang W, Sun Y, Fu Z. TEAD transcription factor family emerges as a promising therapeutic target for oral squamous cell carcinoma. Front Immunol 2024; 15:1480701. [PMID: 39430767 PMCID: PMC11486717 DOI: 10.3389/fimmu.2024.1480701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/17/2024] [Indexed: 10/22/2024] Open
Abstract
The treatment of oral squamous cell carcinoma (OSCC) remains a significant difficulty, as there has been no improvement in survival rates over the past fifty years. Hence, exploration and confirmation of new dependable treatment targets and biomarkers is imperative for OSCC therapy. TEAD transcription factors are crucial for integrating and coordinating multiple signaling pathways that are essential for embryonic development, organ formation, and tissue homeostasis. In addition, by attaching to coactivators, TEAD modifies the expression of genes such as Cyr61, Myc, and connective tissue growth factor, hence facilitating tumor progression. Therefore, TEAD is regarded as an effective predictive biomarker due to its significant connection with clinical parameters in several malignant tumors, including OSCC. The efficacy of existing drugs that specifically target TEAD has demonstrated encouraging outcomes, indicating its potential as an optimal target for OSCC treatment. This review provides an overview of current targeted therapy strategies for OSCC by highlighting the transcription mechanism and involvement of TEAD in oncogenic signaling pathways. Finally, the feasibility of utilizing TEAD as an innovative approach to address OSCC and its potential clinical applications were analyzed and discussed.
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Affiliation(s)
- Shuang Wang
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
- Department of Stomatology, Medical College of Qingdao Huanghai University, Qingdao, China
| | - Dan Shao
- Department of Oral and Maxillofacial Surgery, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, China
| | - Xiaoyan Gao
- Department of Quality Inspection, Traditional Chinese Medical Hospital of Huangdao District, Qingdao, China
| | - Peng Zhao
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Fanzhi Kong
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Jiawei Deng
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Lianzhu Yang
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Wei Shang
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yaping Sun
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Zhiguang Fu
- Department of Tumor Radiotherapy, Air Force Medical Center, People's Liberation Army of China (PLA), Beijing, China
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10
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Li K, Liu L. Computational design and experimental confirmation of a disulfide-stapled YAP helix α1-trap derived from TEAD4 helical hairpin to selectively capture YAP α1-helix with potent antitumor activity. J Comput Aided Mol Des 2024; 38:31. [PMID: 39177727 DOI: 10.1007/s10822-024-00572-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 08/14/2024] [Indexed: 08/24/2024]
Abstract
Human Hippo signaling pathway is an evolutionarily conserved regulator network that controls organ development and has been implicated in various cancers. Transcriptional enhanced associate domain-4 (TEAD4) is the final nuclear effector of Hippo pathway, which is activated by Yes-associated protein (YAP) through binding to two separated YAP regions of α1-helix and Ω-loop. Previous efforts have all been addressed on deriving peptide inhibitors from the YAP to target TEAD4. Instead, we herein attempted to rationally design a so-called 'YAP helixα1-trap' based on the TEAD4 to target YAP by using dynamics simulation and energetics analysis as well as experimental assays at molecular and cellular levels. The trap represents a native double-stranded helical hairpin covering a specific YAP-binding site on TEAD4 surface, which is expected to form a three-helix bundle with the α1-helical region of YAP, thus competitively disrupting TEAD4-YAP interaction. The hairpin was further stapled by a disulfide bridge across its two helical arms. Circular dichroism characterized that the stapling can effectively constrain the trap into a native-like structured conformation in free state, thus largely minimizing the entropy penalty upon its binding to YAP. Affinity assays revealed that the stapling can considerably improve the trap binding potency to YAP α1-helix by up to 8.5-fold at molecular level, which also exhibited a good tumor-suppressing effect at cellular level if fused with TAT cell permeation sequence. In this respect, it is considered that the YAP helixα1-trap-mediated blockade of Hippo pathway may be a new and promising therapeutic strategy against cancers.
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Affiliation(s)
- Kaipeng Li
- School of Chemistry and Chemical Engineering, Jinggangshan University, No. 28, Xueyuan Road, Ji'an, 343009, China
| | - Lijun Liu
- School of Chemistry and Chemical Engineering, Jinggangshan University, No. 28, Xueyuan Road, Ji'an, 343009, China.
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11
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Prencipe G, Cerveró-Varona A, Perugini M, Sulcanese L, Iannetta A, Haidar-Montes AA, Stöckl J, Canciello A, Berardinelli P, Russo V, Barboni B. Amphiregulin orchestrates the paracrine immune-suppressive function of amniotic-derived cells through its interplay with COX-2/PGE 2/EP4 axis. iScience 2024; 27:110508. [PMID: 39156643 PMCID: PMC11326934 DOI: 10.1016/j.isci.2024.110508] [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: 03/06/2024] [Revised: 06/10/2024] [Accepted: 07/11/2024] [Indexed: 08/20/2024] Open
Abstract
The paracrine crosstalk between amniotic-derived membranes (AMs)/epithelial cells (AECs) and immune cells is pivotal in tissue healing following inflammation. Despite evidence collected to date, gaps in understanding the underlying molecular mechanisms have hindered clinical applications. The present study represents a significant step forward demonstrating that amphiregulin (AREG) orchestrates the native immunomodulatory functions of amniotic derivatives via the COX-2/PGE2/EP4 axis. The results highlight the immunosuppressive efficacy of PGE2-dependent AREG release, dampening PBMCs' activation, and NFAT pathway in Jurkat reporter cells via TGF-β signaling. Moreover, AREG emerges as a key protein mediator by attenuating acute inflammatory response in Tg(lysC:DsRed2) zebrafish larvae. Notably, the interplay of diverse COX-2/PGE2 pathway activators enables AM/AEC to adapt rapidly to external stimuli (LPS and/or stretching) through a responsive positive feedback loop on the AREG/EGFR axis. These findings offer valuable insights for developing innovative cell-free therapies leveraging the potential of amniotic derivatives in immune-mediated diseases and regenerative medicine.
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Affiliation(s)
- Giuseppe Prencipe
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Adrián Cerveró-Varona
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Monia Perugini
- Department of Bioscience and Agro-Food and Environmental Technology, University of Teramo, Teramo, Italy
| | - Ludovica Sulcanese
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Annamaria Iannetta
- Department of Bioscience and Agro-Food and Environmental Technology, University of Teramo, Teramo, Italy
| | - Arlette Alina Haidar-Montes
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Johannes Stöckl
- Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna 1090, Austria
| | - Angelo Canciello
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Paolo Berardinelli
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Valentina Russo
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
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12
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Lu M, Zhu M, Wu Z, Liu W, Cao C, Shi J. The role of YAP/TAZ on joint and arthritis. FASEB J 2024; 38:e23636. [PMID: 38752683 DOI: 10.1096/fj.202302273rr] [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: 11/03/2023] [Revised: 04/05/2024] [Accepted: 04/16/2024] [Indexed: 05/21/2024]
Abstract
Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common forms of arthritis with undefined etiology and pathogenesis. Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ), which act as sensors for cellular mechanical and inflammatory cues, have been identified as crucial players in the regulation of joint homeostasis. Current studies also reveal a significant association between YAP/TAZ and the pathogenesis of OA and RA. The objective of this review is to elucidate the impact of YAP/TAZ on different joint tissues and to provide inspiration for further studying the potential therapeutic implications of YAP/TAZ on arthritis. Databases, such as PubMed, Cochran Library, and Embase, were searched for all available studies during the past two decades, with keywords "YAP," "TAZ," "OA," and "RA."
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Affiliation(s)
- Mingcheng Lu
- Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Mengqi Zhu
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Zuping Wu
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Wei Liu
- Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Chuwen Cao
- Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Jiejun Shi
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang, Hangzhou, China
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13
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Liu C, Song Y, Li D, Wang B. Regulation of the tumor immune microenvironment by the Hippo Pathway: Implications for cancer immunotherapy. Int Immunopharmacol 2023; 122:110586. [PMID: 37393838 DOI: 10.1016/j.intimp.2023.110586] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/26/2023] [Accepted: 06/28/2023] [Indexed: 07/04/2023]
Abstract
The tumor immune microenvironment (TIME) is a dynamic and complex ecosystem consisting of immune cells, stromal cells, and tumor cells. It plays a crucial role in shaping cancer progression and treatment outcomes. Notably, tumor-associated immune cells are key regulators within the TIME, influencing immune responses and therapeutic efficacy. The Hippo pathway is a critical signaling pathway involved in the TIME and cancer progression. In this review, we provide an overview of the Hippo pathway's role in the TIME, focusing on its interactions with immune cells and their implications in cancer biology and therapy. Specifically, we discuss the involvement of the Hippo pathway in regulating T-cell function, macrophage polarization, B-cell differentiation, MDSC activity, and dendritic cell-mediated immune responses. Furthermore, we explore its influence on PD-L1 expression in lymphocytes and its potential as a therapeutic target. While recent progress has been made in understanding the Hippo pathway's molecular mechanisms, challenges remain in deciphering its context-dependent effects in different cancers and identifying predictive biomarkers for targeted therapies. By elucidating the intricate crosstalk between the Hippo pathway and the TME, we aim to contribute to the development of innovative strategies for cancer treatment.
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Affiliation(s)
- Chang Liu
- Department of Radiation Oncology, the First Hospital of China Medical University, Shenyang, Liaoning Province, PR China.
| | - Yang Song
- Geriatrics Center, Fourth People's Hospital of Shenyang, Shenyang, Liaoning Province, P.R. China.
| | - DeMing Li
- Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, PR China.
| | - Biao Wang
- Department of Biochemistry and Molecular Biology, School of Life Sciences of China Medical University, Shenyang, Liaoning Province, PR China.
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14
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Feng Z, Fang P, Zheng H, Zhang X. DEP2: an upgraded comprehensive analysis toolkit for quantitative proteomics data. Bioinformatics 2023; 39:btad526. [PMID: 37624922 PMCID: PMC10466079 DOI: 10.1093/bioinformatics/btad526] [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: 02/21/2023] [Revised: 07/14/2023] [Accepted: 08/23/2023] [Indexed: 08/27/2023] Open
Abstract
SUMMARY Mass spectrometry (MS)-based proteomics has become the most powerful approach to study the proteome of given biological and clinical samples. Advancements in sample preparation and MS detection have extended the application of proteomics but have also brought new demands on data analysis. Appropriate proteomics data analysis workflow mainly requires quality control, hypothesis testing, functional mining, and visualization. Although there are numerous tools for each process, an efficient and universal tandem analysis toolkit to obtain a quick overall view of various proteomics data is still urgently needed. Here, we present DEP2, an updated version of DEP we previously established, for proteomics data analysis. We amended the analysis workflow by incorporating alternative approaches to accommodate diverse proteomics data, introducing peptide-protein summarization and coupling biological function exploration. In summary, DEP2 is a well-rounded toolkit designed for protein- and peptide-level quantitative proteomics data. It features a more flexible differential analysis workflow and includes a user-friendly Shiny application to facilitate data analysis. AVAILABILITY AND IMPLEMENTATION DEP2 is available at https://github.com/mildpiggy/DEP2, released under the MIT license. For further information and usage details, please refer to the package website at https://mildpiggy.github.io/DEP2/.
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Affiliation(s)
- Zhenhuan Feng
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Peiyang Fang
- Sanquan College, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Hui Zheng
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510530, China
| | - Xiaofei Zhang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510530, China
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15
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Mokhtari RB, Ashayeri N, Baghaie L, Sambi M, Satari K, Baluch N, Bosykh DA, Szewczuk MR, Chakraborty S. The Hippo Pathway Effectors YAP/TAZ-TEAD Oncoproteins as Emerging Therapeutic Targets in the Tumor Microenvironment. Cancers (Basel) 2023; 15:3468. [PMID: 37444578 DOI: 10.3390/cancers15133468] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/21/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Various cancer cell-associated intrinsic and extrinsic inputs act on YAP/TAZ proteins to mediate the hyperactivation of the TEAD transcription factor-based transcriptome. This YAP/TAZ-TEAD activity can override the growth-limiting Hippo tumor-suppressor pathway that maintains normal tissue homeostasis. Herein, we provide an integrated summary of the contrasting roles of YAP/TAZ during normal tissue homeostasis versus tumor initiation and progression. In addition to upstream factors that regulate YAP/TAZ in the TME, critical insights on the emerging functions of YAP/TAZ in immune suppression and abnormal vasculature development during tumorigenesis are illustrated. Lastly, we discuss the current methods that intervene with the YAP/TAZ-TEAD oncogenic signaling pathway and the emerging applications of combination therapies, gut microbiota, and epigenetic plasticity that could potentiate the efficacy of chemo/immunotherapy as improved cancer therapeutic strategies.
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Affiliation(s)
- Reza Bayat Mokhtari
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Neda Ashayeri
- Division of Hematology and Oncology, Department of Pediatrics, Ali-Asghar Children Hospital, Iran University of Medical Science, Tehran 1449614535, Iran
| | - Leili Baghaie
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Manpreet Sambi
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Kosar Satari
- Division of Hematology and Oncology, Department of Pediatrics, Ali-Asghar Children Hospital, Iran University of Medical Science, Tehran 1449614535, Iran
| | - Narges Baluch
- Department of Immunology and Allergy, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Dmitriy A Bosykh
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Myron R Szewczuk
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Sayan Chakraborty
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
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16
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Li W, Xu P, Kong L, Feng S, Shen N, Huang H, Wang W, Xu X, Wang X, Wang G, Zhang Y, Sun W, Hu W, Liu X. Elabela-APJ axis mediates angiogenesis via YAP/TAZ pathway in cerebral ischemia/reperfusion injury. Transl Res 2023; 257:78-92. [PMID: 36813109 DOI: 10.1016/j.trsl.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/13/2023] [Accepted: 02/02/2023] [Indexed: 02/24/2023]
Abstract
Angiogenesis helps to improve neurological recovery by repairing damaged brain tissue and restoring cerebral blood flow (CBF). The role of the Elabela (ELA)-Apelin receptor (APJ) system in angiogenesis has gained much attention. We aimed to investigate the function of endothelial ELA on postischemic cerebral angiogenesis. Here, we demonstrated that the endothelial ELA expression was upregulated in the ischemic brain and treatment with ELA-32 mitigated brain injury and enhanced the restoration of CBF and newly formed functional vessels following cerebral ischemia/reperfusion (I/R) injury. Furthermore, ELA-32 incubation potentiated proliferation, migration, and tube formation abilities of the mouse brain endothelial cells (bEnd.3 cells) under oxygen-glucose deprivation/reoxygenation (OGD/R) condition. RNA sequencing analysis indicated that ELA-32 incubation had a role in the Hippo signaling pathway, and improved angiogenesis-related gene expression in OGD/R-exposed bEnd.3 cells. Mechanistically, we depicted that ELA could bind to APJ and subsequently activate YAP/TAZ signaling pathway. Silence of APJ or pharmacological blockade of YAP abolished the pro-angiogenesis effects of ELA-32. Together, these findings highlight the ELA-APJ axis as a potential therapeutic strategy for ischemic stroke by showing how activation of this pathway promotes poststroke angiogenesis.
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Affiliation(s)
- Wenyu Li
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Pengfei Xu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
| | - Lingqi Kong
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Shuo Feng
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Nan Shen
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Hongmei Huang
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Wuxuan Wang
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Xiang Xu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Xinyue Wang
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Guoping Wang
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yan Zhang
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Wen Sun
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Wei Hu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Xinfeng Liu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
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17
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Mui CW, Chan WN, Chen B, Cheung AHK, Yu J, Lo KW, Ke H, Kang W, To KF. Targeting YAP1/TAZ in nonsmall-cell lung carcinoma: From molecular mechanisms to precision medicine. Int J Cancer 2023; 152:558-571. [PMID: 35983734 DOI: 10.1002/ijc.34249] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/28/2022] [Accepted: 08/08/2022] [Indexed: 02/01/2023]
Abstract
Accumulating evidence has underscored the importance of the Hippo-YAP1 signaling in lung tissue homeostasis, whereas its deregulation induces tumorigenesis. YAP1 and its paralog TAZ are the key downstream effectors tightly controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In solid tumors, Hippo-YAP1 crosstalks with other signaling pathways such as Wnt/β-catenin, receptor tyrosine kinase cascade, Notch and TGF-β to synergistically drive tumorigenesis. As YAP1/TAZ expression is significantly correlated with unfavorable outcomes for the patients, small molecules have been developed for targeting YAP1/TAZ to get a therapeutic effect. In this review, we summarize the recent findings on the deregulation of Hippo-YAP1 pathway in nonsmall cell lung carcinoma, discuss the molecular mechanisms of its dysregulation in leading to tumorigenesis, explore the therapeutic strategies for targeting YAP1/TAZ, and provide the research directions for deep investigation. We believe that detailed delineation of Hippo-YAP1 regulation in tumorigenesis provides novel insight for accurate therapeutic intervention.
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Affiliation(s)
- Chun Wai Mui
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of 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, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Wai Nok Chan
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of 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, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of 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, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Alvin Ho-Kwan Cheung
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of 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, SAR, People's Republic of China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Huixing Ke
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of 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, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of 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, SAR, People's Republic of China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
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18
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Chen X, Adhikary G, Ma E, Newland JJ, Naselsky W, Xu W, Eckert RL. Sulforaphane inhibits CD44v6/YAP1/TEAD signaling to suppress the cancer phenotype. Mol Carcinog 2023; 62:236-248. [PMID: 36285644 PMCID: PMC9851963 DOI: 10.1002/mc.23479] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 01/25/2023]
Abstract
Sulforaphane (SFN) is a promising cancer prevention and treatment agent that strongly suppresses the cutaneous squamous cell carcinoma (CSCC) cell cancer phenotype. We previously showed that yes-associated protein 1 (YAP1)/TEAD signaling is a key procancer stimulator of the aggressive CSCC cell cancer phenotype. However, SFN-responsive upstream regulators of YAP1/TEAD signaling are not well characterized and so there is a pressing need to identify these factors. We show that CD44v6 knockdown reduces YAP1/TEAD-dependent transcription and target gene expression, and that this is associated with reduced spheroid formation, invasion and migration. CD44v6 knockout cell lines also display reduced YAP1/TEAD activity and target gene expression and attenuated spheroid formation, invasion, migration and tumor formation. An important finding is that SFN treatment suppresses CD44v6 level leading to a reduction in YAP1/TEAD signaling and marker gene expression. Sox2 level and epithelial-mesenchymal transition (EMT) are also reduced. Forced expression of constitutive active YAP1 in CD44v6 knockdown cells partially restores the aggressive cancer phenotype. These important findings suggest that CD44v6 drives YAP1/TEAD signaling to enhance the CSCC cell cancer phenotype and that SFN treatment reduces CD44v6 level/function which, in turn, reduces YAP1/TEAD signaling leading to reduced stemness, EMT and tumor growth.
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Affiliation(s)
- Xi Chen
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Gautam Adhikary
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Emily Ma
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - John J. Newland
- Department of Surgery Division of Thoracic Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Warren Naselsky
- Department of Surgery Division of Thoracic Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Wen Xu
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Richard L. Eckert
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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19
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Huang W, Wu X, Zhao Y, Liu Y, Zhang B, Qiao M, Zhu Z, Zhao Z. Janus-Inspired Core-Shell Structure Hydrogel Programmatically Releases Melatonin for Reconstruction of Postoperative Bone Tumor. ACS APPLIED MATERIALS & INTERFACES 2023; 15:2639-2655. [PMID: 36603840 PMCID: PMC9869893 DOI: 10.1021/acsami.2c18545] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/26/2022] [Indexed: 06/17/2023]
Abstract
At present, surgery is one of the main treatments for bone tumor. However, the risk of recurrence and the large area of bone defects after surgery pose a great challenge. Therefore, a Janus-inspired core-shell structure bone scaffold was designed to achieve the self-programmed release of melatonin at different concentrations, clearing the residual tumor cells at early stage after resection and promoting bone repair later. The layered differential load designs inspired by Janus laid the foundation for the differential release of melatonin, where sufficient melatonin inhibited tumor growth as low dose promoted osteogenesis. Then, the automatically programmed delivery of melatonin is achieved by the gradient degradation of the core-shell structure. In the material characterization, scanning electron microscopy revealed the core-shell structure. The drug release experiment and in vivo degradation experiment reflected the programmed differential release of melatonin. In the biological experiment part, in vivo and in vitro experiments not only confirmed the significant inhibitory effect of the core-shell hydrogel scaffold on tumor but also confirmed its positive effect on osteogenesis. Our Janus-inspired core-shell hydrogel scaffold provides a safe and efficient means to inhibit tumor recurrence and bone repair after bone tumor, and it also develops a new and efficient tool for differential and programmed release of other drugs.
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Affiliation(s)
- Wei Huang
- State Key Laboratory of Oral
Diseases & National Clinical Research Center for Oral Diseases,
West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, People’s Republic
of China
| | - Xiaoyue Wu
- State Key Laboratory of Oral
Diseases & National Clinical Research Center for Oral Diseases,
West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, People’s Republic
of China
| | - Yifan Zhao
- State Key Laboratory of Oral
Diseases & National Clinical Research Center for Oral Diseases,
West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, People’s Republic
of China
| | - Yanhua Liu
- State Key Laboratory of Oral
Diseases & National Clinical Research Center for Oral Diseases,
West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, People’s Republic
of China
| | - Bo Zhang
- State Key Laboratory of Oral
Diseases & National Clinical Research Center for Oral Diseases,
West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, People’s Republic
of China
| | - Mingxin Qiao
- State Key Laboratory of Oral
Diseases & National Clinical Research Center for Oral Diseases,
West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, People’s Republic
of China
| | - Zhou Zhu
- State Key Laboratory of Oral
Diseases & National Clinical Research Center for Oral Diseases,
West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, People’s Republic
of China
| | - Zhihe Zhao
- State Key Laboratory of Oral
Diseases & National Clinical Research Center for Oral Diseases,
West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, People’s Republic
of China
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20
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Ma FY, Zhou XH, Liang Q. Advances in understanding of role and mechanism of Hippo signaling pathway in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2023; 31:14-19. [DOI: 10.11569/wcjd.v31.i1.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors, and most patients have a poor prognosis. Many studies have shown that the Hippo signaling pathway plays a key role in the occurrence and development of CRC by regulating CRC cell proliferation and apoptosis, tumor invasion and metastasis, autophagy, metabolic reprogramming, drug resistance, and other processes. This article reviews the latest progress in research of the expression of key molecules of the Hippo signaling pathway in CRC as well as the understanding of the mechanism by which this pathway regulates the occurrence and development of CRC.
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Affiliation(s)
- Fu-Yan Ma
- Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Xi-Han Zhou
- Department of Gastroenterology, Affiliated Hospital of Youjiang Medical College Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Qiao Liang
- Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
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21
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Lou J, Lu Y, Cheng J, Zhou F, Yan Z, Zhang D, Meng X, Zhao Y. A chemical perspective on the modulation of TEAD transcriptional activities: Recent progress, challenges, and opportunities. Eur J Med Chem 2022; 243:114684. [DOI: 10.1016/j.ejmech.2022.114684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/02/2022] [Accepted: 08/11/2022] [Indexed: 11/30/2022]
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22
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Lee JH, Kwon M, Lim WY, Yoo CR, Yoon Y, Han D, Ahn JH, Yoon K. YAP inhibits HCMV replication by impairing STING-mediated nuclear transport of the viral genome. PLoS Pathog 2022; 18:e1011007. [PMID: 36455047 PMCID: PMC9746980 DOI: 10.1371/journal.ppat.1011007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 12/13/2022] [Accepted: 11/17/2022] [Indexed: 12/05/2022] Open
Abstract
YES-associated protein (YAP), a critical actor of the mammalian Hippo signaling pathway involved in diverse biological events, has gained increased recognition as a cellular factor regulated by viral infections, but very few studies have investigated their relationship vice versa. In this study, we show that YAP impairs HCMV replication as assessed by viral gene expression analysis and progeny assays, and that this inhibition occurs at the immediate-early stages of the viral life cycle, at the latest. Using YAP mutants lacking key functional domains and shRNA against TEAD, we show that the inhibitory effects of YAP on HCMV replication are nuclear localization- and TEAD cofactor-dependent. Quantitative real-time PCR (qPCR) and subcellular fractionation analyses reveal that YAP does not interfere with the viral entry process but inhibits transport of the HCMV genome into the nucleus. Most importantly, we show that the expression of stimulator of interferon genes (STING), recently identified as an important component for nuclear delivery of the herpesvirus genome, is severely downregulated by YAP at the level of gene transcription. The functional importance of STING is further confirmed by the observation that STING expression restores YAP-attenuated nuclear transport of the HCMV genome, viral gene expression, and progeny virus production. We also show that HCMV-upregulated YAP reduces expression of STING. Taken together, these findings indicate that YAP possesses both direct and indirect regulatory roles in HCMV replication at different infection stages.
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Affiliation(s)
- Ju Hyun Lee
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, South Korea
| | - Mookwang Kwon
- College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, South Korea
| | - Woo Young Lim
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, South Korea
| | - Chae Rin Yoo
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, South Korea
| | - Youngik Yoon
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, South Korea
| | - Dasol Han
- College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, South Korea
| | - Jin-Hyun Ahn
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Sungkyunkwan University, Suwon, South Korea
| | - Keejung Yoon
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, South Korea
- College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, South Korea
- * E-mail:
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23
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Pei Z, Qin Y, Fu X, Yang F, Huo F, Liang X, Wang S, Cui H, Lin P, Zhou G, Yan J, Wu J, Chen ZN, Zhu P. Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model. Redox Biol 2022; 57:102509. [PMID: 36302319 PMCID: PMC9614651 DOI: 10.1016/j.redox.2022.102509] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 10/10/2022] [Indexed: 11/30/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by excessive proliferation of fibroblasts and excessive accumulation of extracellular matrix (ECM). Ferroptosis is a novel form of cell death characterized by the lethal accumulation of iron and lipid peroxidation, which is associated with many diseases. Our study addressed the potential role played by ferroptosis and iron accumulation in the progression of pulmonary fibrosis. We found that the inducers of pulmonary fibrosis and injury, namely, bleomycin (BLM) and lipopolysaccharide (LPS), induced ferroptosis of lung epithelial cells. Both the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) alleviated the symptoms of pulmonary fibrosis induced by bleomycin or LPS. TGF-β stimulation upregulated the expression of transferrin receptor protein 1 (TFRC) in the human lung fibroblast cell line (MRC-5) and mouse primary lung fibroblasts, resulting in increased intracellular Fe2+, which promoted the transformation of fibroblasts into myofibroblasts. Mechanistically, TGF-β enhanced the expression and nuclear localization of the transcriptional coactivator tafazzin (TAZ), which combined with the transcription factor TEA domain protein (TEAD)-4 to promote the transcription of TFRC. In addition, elevated Fe2+ failed to induce the ferroptosis of fibroblasts, which might be related to the regulation of iron export and lipid metabolism. Finally, we specifically knocked out TFRC expression in fibroblasts in mice, and compared with those in the control mice, the symptoms of pulmonary fibrosis were reduced in the knockout mice after bleomycin induction. Collectively, these findings suggest the therapeutic potential of ferroptosis inhibitors and iron chelators in treating pulmonary fibrosis.
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Affiliation(s)
- Zhuo Pei
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yifei Qin
- Guangzhou (Jinan) Biomedical Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Xianghui Fu
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Fengfan Yang
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Fei Huo
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Xue Liang
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Shijie Wang
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Hongyong Cui
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Peng Lin
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Gang Zhou
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Jiangna Yan
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Jiao Wu
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
| | - Zhi-Nan Chen
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
| | - Ping Zhu
- National Translational Science Center for Molecular Medicine and Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
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24
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Fan M, Lu W, Che J, Kwiatkowski NP, Gao Y, Seo HS, Ficarro SB, Gokhale PC, Liu Y, Geffken EA, Lakhani J, Song K, Kuljanin M, Ji W, Jiang J, He Z, Tse J, Boghossian AS, Rees MG, Ronan MM, Roth JA, Mancias JD, Marto JA, Dhe-Paganon S, Zhang T, Gray NS. Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling. eLife 2022; 11:e78810. [PMID: 36300789 PMCID: PMC9728995 DOI: 10.7554/elife.78810] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 10/26/2022] [Indexed: 11/13/2022] Open
Abstract
The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.
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Affiliation(s)
- Mengyang Fan
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
- Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouChina
| | - Wenchao Lu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
- Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford UniversityStanfordUnited States
| | - Jianwei Che
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
| | - Nicholas P Kwiatkowski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
| | - Yang Gao
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
| | - Hyuk-Soo Seo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
| | - Scott B Ficarro
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
| | - Prafulla C Gokhale
- Experimental Therapeutics Core, Dana-Farber Cancer InstituteBostonUnited States
| | - Yao Liu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
| | - Ezekiel A Geffken
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
| | - Jimit Lakhani
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
| | - Kijun Song
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
| | - Miljan Kuljanin
- Department of Cell Biology, Harvard Medical SchoolBostonUnited States
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana- Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
| | - Wenzhi Ji
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
- Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford UniversityStanfordUnited States
| | - Jie Jiang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
| | - Zhixiang He
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
| | - Jason Tse
- Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford UniversityStanfordUnited States
| | | | - Matthew G Rees
- Broad Institute of MIT and HarvardCambridgeUnited States
| | | | | | - Joseph D Mancias
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana- Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
| | - Jarrod A Marto
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
| | - Sirano Dhe-Paganon
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
| | - Tinghu Zhang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
- Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford UniversityStanfordUnited States
| | - Nathanael S Gray
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUnited States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolBostonUnited States
- Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford UniversityStanfordUnited States
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25
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Furet P, Bordas V, Le Douget M, Salem B, Mesrouze Y, Imbach-Weese P, Sellner H, Voegtle M, Soldermann N, Chapeau E, Wartmann M, Scheufler C, Fernandez C, Kallen J, Guagnano V, Chène P, Schmelzle T. The First Class of Small Molecules Potently Disrupting the YAP-TEAD Interaction by Direct Competition. ChemMedChem 2022; 17:e202200303. [PMID: 35950546 DOI: 10.1002/cmdc.202200303] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/10/2022] [Indexed: 11/08/2022]
Abstract
Inhibition of the YAP-TEAD protein protein interaction is an attractive therapeutic concept under intense investigation with the objective to treat cancers associated with a dysregulation of the Hippo pathway. However, owing to the very extended surface of interaction of the two proteins, the identification of small drug-like molecules able to efficiently prevent YAP from binding to TEAD by direct competition has been elusive so far. We disclose here the discovery of the first class of small molecules potently inhibiting the YAP-TEAD interaction by binding at one of the main interaction sites of YAP at the surface of TEAD. These inhibitors, providing a path forward to pharmacological intervention in the Hippo pathway, evolved from a weakly active virtual screening hit advanced to high potency by structure-based design.
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Affiliation(s)
- Pascal Furet
- Novartis Pharma AG, Biomedical Research, 4002, Basel, SWITZERLAND
| | - Vincent Bordas
- Novartis Institutes for BioMedical Research Basel, GDC, SWITZERLAND
| | | | - Bahaa Salem
- Novartis Institutes for BioMedical Research Basel, GDC, SWITZERLAND
| | - Yannick Mesrouze
- Novartis Institutes for BioMedical Research Basel, ODD, SWITZERLAND
| | | | - Holger Sellner
- Novartis Institutes for BioMedical Research Basel, GDC, SWITZERLAND
| | - Markus Voegtle
- Novartis Institutes for BioMedical Research Basel, GDC, SWITZERLAND
| | | | - Emilie Chapeau
- Novartis Institutes for BioMedical Research Basel, ODD, SWITZERLAND
| | - Markus Wartmann
- Novartis Institutes for BioMedical Research Basel, ODD, SWITZERLAND
| | | | - Cesar Fernandez
- Novartis Institutes for BioMedical Research Basel, CBT, SWITZERLAND
| | - Joerg Kallen
- Novartis Institutes for BioMedical Research Basel, CBT, SWITZERLAND
| | - Vito Guagnano
- Novartis Institutes for BioMedical Research Basel, GDC, SWITZERLAND
| | - Patrick Chène
- Novartis Institutes for BioMedical Research Basel, ODD, SWITZERLAND
| | - Tobias Schmelzle
- Novartis Institutes for BioMedical Research Basel, ODD, SWITZERLAND
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26
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Zhang J, Tong Y, Lu X, Dong F, Ma X, Yin S, He Y, Liu Y, Liu Q, Fan D. A derivant of ginsenoside CK and its inhibitory effect on hepatocellular carcinoma. Life Sci 2022; 304:120698. [PMID: 35690105 DOI: 10.1016/j.lfs.2022.120698] [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: 04/10/2022] [Revised: 05/30/2022] [Accepted: 06/05/2022] [Indexed: 11/25/2022]
Abstract
Epidemiological studies have shown that hepatocellular carcinoma (HCC) is a main cause of tumor death worldwide. Accumulating data indicate that ginsenoside CK is an effective compound for preventing HCC growth and development. However, improvement of pharmaceutical effect of the ginsenoside CK is still needed. In our study, we performed acetylation of ginsenoside CK (CK-3) and investigated the antitumor effects of the derivative in vitro and in vivo. The cytotoxicity analysis revealed that compared with CK, CK-3 could inhibit the proliferation of multiple tumor cell lines at a lower concentration. Treating with CK-3 on HCC cells arrested cell cycle in G2/M phase and induced cell apoptosis through AO/EB staining, TUNEL analysis and flow cytometry. Meanwhile, CK-3 significantly inhibited tumor growth in an HCC xenograft model and showed no side effect on the function of the main organs. Mechanistically, whole transcriptome analysis revealed that the antitumor effect of CK-3 was involved in the Hippo signaling pathway. The immunoblotting and immunofluorescence results illustrated that CK-3 directly facilitated the phosphorylation of YAP1 and decreased the expression of the main transcription factor TEAD2 in HCC cell lines and tumor tissue sections. Collectively, our results demostrate the formation of a new derivative of ginsenoside CK and its regulatory mechanism in HCC, which could activate the Hippo-YAP1-TEAD2 signaling pathway to regulate HCC progression. This research could provide a new direction for traditional Chinese medicine in the therapy of tumors.
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Affiliation(s)
- Jingjing Zhang
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Yangliu Tong
- Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Xun Lu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Fangming Dong
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Xiaoxuan Ma
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Shiyu Yin
- Shaanxi Giant Biotechnology Co., LTD, No. 20, Zone C, Venture R&D Park, No. 69, Jinye Road, High-tech Zone, Xi'an, Shaanxi 710076, China
| | - Ying He
- Shaanxi Giant Biotechnology Co., LTD, No. 20, Zone C, Venture R&D Park, No. 69, Jinye Road, High-tech Zone, Xi'an, Shaanxi 710076, China
| | - Yonghong Liu
- Shaanxi Giant Biotechnology Co., LTD, No. 20, Zone C, Venture R&D Park, No. 69, Jinye Road, High-tech Zone, Xi'an, Shaanxi 710076, China
| | - Qingchao Liu
- Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China.
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China.
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27
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Peisker F, Halder M, Nagai J, Ziegler S, Kaesler N, Hoeft K, Li R, Bindels EMJ, Kuppe C, Moellmann J, Lehrke M, Stoppe C, Schaub MT, Schneider RK, Costa I, Kramann R. Mapping the cardiac vascular niche in heart failure. Nat Commun 2022; 13:3027. [PMID: 35641541 PMCID: PMC9156759 DOI: 10.1038/s41467-022-30682-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/11/2022] [Indexed: 02/08/2023] Open
Abstract
The cardiac vascular and perivascular niche are of major importance in homeostasis and during disease, but we lack a complete understanding of its cellular heterogeneity and alteration in response to injury as a major driver of heart failure. Using combined genetic fate tracing with confocal imaging and single-cell RNA sequencing of this niche in homeostasis and during heart failure, we unravel cell type specific transcriptomic changes in fibroblast, endothelial, pericyte and vascular smooth muscle cell subtypes. We characterize a specific fibroblast subpopulation that exists during homeostasis, acquires Thbs4 expression and expands after injury driving cardiac fibrosis, and identify the transcription factor TEAD1 as a regulator of fibroblast activation. Endothelial cells display a proliferative response after injury, which is not sustained in later remodeling, together with transcriptional changes related to hypoxia, angiogenesis, and migration. Collectively, our data provides an extensive resource of transcriptomic changes in the vascular niche in hypertrophic cardiac remodeling.
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Affiliation(s)
- Fabian Peisker
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Medical Faculty, Aachen, Germany
| | - Maurice Halder
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Medical Faculty, Aachen, Germany
| | - James Nagai
- Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
- Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Susanne Ziegler
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Medical Faculty, Aachen, Germany
| | - Nadine Kaesler
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Medical Faculty, Aachen, Germany
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Medical Faculty, Aachen, Germany
| | - Konrad Hoeft
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Medical Faculty, Aachen, Germany
| | - Ronghui Li
- Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
- Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Eric M J Bindels
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Christoph Kuppe
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Medical Faculty, Aachen, Germany
| | - Julia Moellmann
- Department of Cardiology, RWTH Aachen University Hospital, Aachen, Germany
| | - Michael Lehrke
- Department of Cardiology, RWTH Aachen University Hospital, Aachen, Germany
| | - Christian Stoppe
- Department of Anesthesiology, Intensive Care, Emergency, and Pain Medicine, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Michael T Schaub
- Department of Computer Science, RWTH Aachen University, Aachen, Germany
| | | | - Ivan Costa
- Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
- Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Rafael Kramann
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Medical Faculty, Aachen, Germany.
- Institute of Cell Biology, RWTH Aachen University Hospital, Aachen, Germany.
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands.
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Seeneevassen L, Dubus P, Gronnier C, Varon C. Hippo in Gastric Cancer: From Signalling to Therapy. Cancers (Basel) 2022; 14:cancers14092282. [PMID: 35565411 PMCID: PMC9105983 DOI: 10.3390/cancers14092282] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/12/2022] [Accepted: 04/20/2022] [Indexed: 12/12/2022] Open
Abstract
The Hippo pathway is one of the most important ones in mammals. Its key functions in cell proliferation, tissue growth, repair, and homeostasis make it the most crucial one to be controlled. Many means have been deployed for its regulation, since this pathway is not only composed of core regulatory components, but it also communicates with and regulates various other pathways, making this signalisation even more complex. Its role in cancer has been studied more and more over the past few years, and it presents YAP/TAZ as the major oncogenic actors. In this review, we relate how vital this pathway is for different organs, and how regulatory mechanisms have been bypassed to lead to cancerous states. Most studies present an upregulation status of YAP/TAZ, and urge the need to target them. A focus is made here on gastric carcinogenesis, its main dysregulations, and the major strategies adopted and tested to counteract Hippo pathway disbalance in this disease. Hippo pathway targeting can be achieved by various means, which are described in this review. Many studies have tested different potential molecules, which are detailed hereby. Though not all tested in gastric cancer, they could represent a real interest.
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Affiliation(s)
- Lornella Seeneevassen
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
| | - Pierre Dubus
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Department of Histology and Pathology, CHU Bordeaux, F-33000 Bordeaux, France
| | - Caroline Gronnier
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Department of Digestive Surgery, Haut-Lévêque Hospital, CHU Bordeaux, F-33000 Bordeaux, France
| | - Christine Varon
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Correspondence:
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29
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Feichtinger M, Beier A, Migotti M, Schmid M, Bokhovchuk F, Chène P, Konrat R. Long-range structural preformation in yes-associated protein precedes encounter complex formation with TEAD. iScience 2022; 25:104099. [PMID: 35378854 PMCID: PMC8976148 DOI: 10.1016/j.isci.2022.104099] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/25/2022] [Accepted: 03/15/2022] [Indexed: 11/22/2022] Open
Abstract
Yes-associated protein (YAP) is a partly intrinsically disordered protein (IDP) that plays a major role as the downstream element of the Hippo pathway. Although the structures of the complex between TEA domain transcription factors (TEADs) and the TEAD-binding domain of YAP are already well characterized, its apo state and the binding mechanism with TEADs are still not clearly defined. Here we characterize via a combination of different NMR approaches with site-directed mutagenesis and affinity measurements the intrinsically disordered solution state of apo YAP. Our results provide evidence that the apo state of YAP adopts several compact conformations that may facilitate the formation of the YAP:TEAD complex. The interplay between local secondary structure element preformation and long-range co-stabilization of these structured elements precedes the encounter complex formation with TEAD and we, therefore, propose that TEAD binding proceeds largely via conformational selection of the preformed compact substates displaying at least nanosecond lifetimes.
Secondary structure elements are preformed in apo YAP Preformation of secondary structure elements is co-dependent Apo YAP exhibits long-range structural compaction YAP compaction has a kinetic contribution to the YAP:TEAD formation
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Affiliation(s)
- Michael Feichtinger
- Department of Computational and Structural Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria
| | - Andreas Beier
- Department of Computational and Structural Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria
| | - Mario Migotti
- Department of Computational and Structural Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria
| | - Matthias Schmid
- Department of Computational and Structural Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria
| | - Fedir Bokhovchuk
- Ichnos Sciences SA, Route de la Corniche 5A, 1066 Epalinges, Switzerland
| | - Patrick Chène
- Novartis Pharma AG, Postfach WSJ 386.4, 4002 Basel, Switzerland
| | - Robert Konrat
- Department of Computational and Structural Biology, Max Perutz Labs, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria
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Sun X, Hou Z, Li N, Zhang S. MiR-597-5p suppresses the progression of hepatocellular carcinoma via targeting transcriptional enhancer associate domain transcription factor 1 (TEAD1). In Vitro Cell Dev Biol Anim 2022; 58:96-108. [PMID: 35169903 DOI: 10.1007/s11626-021-00614-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 08/01/2021] [Indexed: 11/05/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high incidence and mortality. MiR-597-5p is downregulated in tumor tissues of HCC compared with non-tumor tissues. However, its role in HCC is still unknown. This study aims to assess the function of miR-597-5p in HCC development and investigate the underlying mechanism. To perform gain- and loss-of-function studies, SK-HEP-1 cells and Huh-7 cells were transfected with miR-597-5p mimics and inhibitor, respectively. MiR-597-5p markedly reduced the cell viability and the expression of Ki-67 in HCC cells. MiR-597-5p also repressed the cell cycle progression of HCC cells and the protein levels of cyclin D1 and CDK2. Moreover, miR597-5p inhibited the migration and invasion of HCC cells and decreased MMP2 and MMP9 levels. Transcriptional enhancer associate domain transcription factor 1 (TEAD1) was identified as a target of miR-597-5p by luciferase reporter assay. TEAD1 and its downstream target genes, CTGF and CYR61, were downregulated by miR-597-5p in HCC cells. Furthermore, miR-597-5p was demonstrated to function in HCC progression by targeting TEAD1 via TEAD1 expression gain and loss. Our study demonstrates that miR-597-5p represses the proliferation, migration, and invasion of HCC cells through targeting TEAD1, which provides a therapeutic target for HCC treatment.
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Affiliation(s)
- Xiaogang Sun
- The Second Department of General Surgery, Jincheng People's Hospital, 456 Wenchang East Street, Jincheng, 048026, Shanxi, China
| | - Zhiyun Hou
- The Second Department of General Surgery, Jincheng People's Hospital, 456 Wenchang East Street, Jincheng, 048026, Shanxi, China.
| | - Ning Li
- The Second Department of General Surgery, Jincheng People's Hospital, 456 Wenchang East Street, Jincheng, 048026, Shanxi, China
| | - Shuangwei Zhang
- The Second Department of General Surgery, Jincheng People's Hospital, 456 Wenchang East Street, Jincheng, 048026, Shanxi, China
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31
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Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library. Pharmaceutics 2022; 14:pharmaceutics14020391. [PMID: 35214125 PMCID: PMC8878929 DOI: 10.3390/pharmaceutics14020391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/24/2022] [Accepted: 01/28/2022] [Indexed: 01/25/2023] Open
Abstract
The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.
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32
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The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises. Int J Mol Sci 2021; 23:ijms23010430. [PMID: 35008857 PMCID: PMC8745604 DOI: 10.3390/ijms23010430] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/14/2022] Open
Abstract
The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways’ role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.
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33
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Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine. Cells 2021; 10:cells10102715. [PMID: 34685695 PMCID: PMC8534579 DOI: 10.3390/cells10102715] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/01/2021] [Accepted: 10/01/2021] [Indexed: 12/16/2022] Open
Abstract
The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1–4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein–protein interaction (PPI) with TEAD1–4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ–TEAD-dependent transcription in cancer.
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34
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Iftikhar R, Zahoor AF, Irfan M, Rasul A, Rao F. Synthetic molecules targeting yes associated protein activity as chemotherapeutics against cancer. Chem Biol Drug Des 2021; 98:1025-1037. [PMID: 34587361 DOI: 10.1111/cbdd.13960] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/09/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022]
Abstract
The Hippo signaling pathway extorts several signals that concomitantly target the activity of transcriptional cofactor yes associated protein (YAP). YAP is a key regulator that elicits signature gene expression by coupling with transcriptional enhanced associate domain (TEAD) family of transcriptional factors. The YAP-TEAD complex via target gene expression gets associated with the development, proliferation, and progression of cancerous cells. Moreover, YAP adorns cells with several oncogenic traits such as inhibition of apoptosis, enhanced proliferation, drug resistance, and immune response suppression, which later became associated with various diseases, particularly cancer. Therefore, inhibition of the YAP activity is an appealing and viable therapeutic target for cancer treatment. This review highlights the recent advances in existing and novel synthetic therapeutics targeting YAP inhibition and regulation. The synthetically produced YAPD93A belonging to cyclic peptides and DC-TEADin02 and vinyl sulfonamide class of compounds are the most potent compounds to inhibit the YAP-TEAD expression by targeting protein-protein interaction (IC50 = 25 nM) and palmitate binding central pocket of TEAD (IC50 = 197 nM), respectively. On the other hand, Chlorpromazine belonging to phenothiazines class has the least potential to suppress YAP via proteasomal degradation (cell viability value of <20% at 40 µM).
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Affiliation(s)
- Ramsha Iftikhar
- Department of Chemistry, Government College University Faisalabad, Faisalabad, Pakistan
| | - Ameer Fawad Zahoor
- Department of Chemistry, Government College University Faisalabad, Faisalabad, Pakistan
| | - Muhammad Irfan
- Department of Pharmaceutics, Government College University Faisalabad, Faisalabad, Pakistan
| | - Azhar Rasul
- Department of Zoology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Faiza Rao
- Fujian Provincial Key Laboratory of Reproduction Health Research, School of Medicine, Xiamen University, Xiamen, China
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35
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Zhang D, Wu H, Zhao J. Computational design and experimental substantiation of conformationally constrained peptides from the complex interfaces of transcriptional enhanced associate domains with their cofactors in gastric cancer. Comput Biol Chem 2021; 94:107569. [PMID: 34500324 DOI: 10.1016/j.compbiolchem.2021.107569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 08/08/2021] [Accepted: 08/26/2021] [Indexed: 11/16/2022]
Abstract
Transcriptional enhanced associate domains (Teads) are the downstream effectors of the hippo signaling pathway and have been recognized as attractive druggable targets of gastric cancer. The biological function of Teads is regulated by diverse cofactors. In this study, the intermolecular interactions of Teads with their cognate cofactors were systematically characterized at structural, thermodynamic and dynamic levels. The Teads possess a double-stranded helical hairpin that is surrounded by three independent structural elements β-sheet, α-helix and Ω-loop of cofactor proteins and plays a central role in recognition and association with cofactors. A number of functional peptides were split from the hairpin region at Tead-cofactor complex interfaces, which, however, cannot maintain in native conformation without the support of protein context and would therefore incur a considerable entropy penalty upon competitively rebinding to the interfaces. Here, we further used disulfide and hydrocarbon bridges to cyclize and staple the hairpin and helical peptides, respectively. The chemical modification strategies were demonstrated to effectively constrain peptide conformation into active state and to largely reduce peptide flexibility in free state, thus considerably improving their affinity. Since the cyclization and stapling only minimize the indirect entropy cost but do not influence the direct enthalpy effect upon peptide binding, the designed conformationally constrained peptides can retain in their native selectivity over different cofactors. This is particularly interesting because it means that the cyclized/stapled, affinity-improved peptides can specifically compete with their parent Teads for the cofactor arrays as they share consistent target specificity.
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Affiliation(s)
- Donglei Zhang
- Department of Pharmacy, Cangzhou Central Hospital, Hebei Medical University, Cangzhou 061014, China
| | - Hongna Wu
- Cangzhou Institute for Food and Drug Control, Cangzhou 061003, China
| | - Jing Zhao
- Department of Pharmacy, Cangzhou Central Hospital, Hebei Medical University, Cangzhou 061014, China.
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36
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Wu Y, Aegerter P, Nipper M, Ramjit L, Liu J, Wang P. Hippo Signaling Pathway in Pancreas Development. Front Cell Dev Biol 2021; 9:663906. [PMID: 34079799 PMCID: PMC8165189 DOI: 10.3389/fcell.2021.663906] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/12/2021] [Indexed: 12/17/2022] Open
Abstract
The Hippo signaling pathway is a vital regulator of pancreatic development and homeostasis, directing cell fate decisions, morphogenesis, and adult pancreatic cellular plasticity. Through loss-of-function research, Hippo signaling has been found to play key roles in maintaining the proper balance between progenitor cell renewal, proliferation, and differentiation in pancreatic organogenesis. Other studies suggest that overactivation of YAP, a downstream effector of the pathway, promotes ductal cell development and suppresses endocrine cell fate specification via repression of Ngn3. After birth, disruptions in Hippo signaling have been found to lead to de-differentiation of acinar cells and pancreatitis-like phenotype. Further, Hippo signaling directs pancreatic morphogenesis by ensuring proper cell polarization and branching. Despite these findings, the mechanisms through which Hippo governs cell differentiation and pancreatic architecture are yet to be fully understood. Here, we review recent studies of Hippo functions in pancreatic development, including its crosstalk with NOTCH, WNT/β-catenin, and PI3K/Akt/mTOR signaling pathways.
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Affiliation(s)
- Yifan Wu
- Department of Cell Systems and Anatomy, The University of Texas Health San Antonio, San Antonio, TX, United States.,Department of Obstetrics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Pauline Aegerter
- Department of Cell Systems and Anatomy, The University of Texas Health San Antonio, San Antonio, TX, United States
| | - Michael Nipper
- Department of Cell Systems and Anatomy, The University of Texas Health San Antonio, San Antonio, TX, United States
| | - Logan Ramjit
- Department of Cell Systems and Anatomy, The University of Texas Health San Antonio, San Antonio, TX, United States
| | - Jun Liu
- Department of Cell Systems and Anatomy, The University of Texas Health San Antonio, San Antonio, TX, United States
| | - Pei Wang
- Department of Cell Systems and Anatomy, The University of Texas Health San Antonio, San Antonio, TX, United States
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37
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Niki Y, Kobayashi Y, Moriyama K. Expression pattern of transcriptional enhanced associate domain family member 1 (Tead1) in developing mouse molar tooth. Gene Expr Patterns 2021; 40:119182. [PMID: 33984529 DOI: 10.1016/j.gep.2021.119182] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/24/2021] [Accepted: 04/27/2021] [Indexed: 11/16/2022]
Abstract
The Hippo pathway is essential for determining organ size by regulating cell proliferation. Previous reports have shown that impairing this pathway causes abnormal tooth development. However, the precise expression profile of the members of the transcriptional enhanced associate domain family (Tead), which are key transcription factors mediating Yap function, during tooth development is unclear. In this study, among the four isoforms of Tead (Tead1 - 4), only the expression of Tead1 mRNA was observed using semiquantitative RT- PCR in murine developing tooth germ at E16.5. The expression level of Tead1 mRNA in the excised murine mandibular molar tooth germ was significantly higher at E16.5 than at other developmental stages, as determined using quantitative PCR. We found that the mRNA expression of connective tissue growth factor (Ctgf), which is one of the Yap target genes directly controlling cell growth, changed consistently with that of Tead1 in developing molars. Fluorescent immunostaining revealed that Tead1 protein was expressed in both epithelial cells and mesenchymal cells of the dental lamina and dental epithelium, including the primary enamel knot during the cap stage. During the early bell stage (E16.5), Tead1 was expressed intensely in the inner and outer enamel epithelium, including the secondary enamel knot and the neighboring mesenchymal cells. Tead1 then specifically localized to the inner and outer enamel epithelium, which is responsible for enamel formation during the bell stage. These expression patterns were consistent with those of Yap, Taz, and Ctgf protein in developing molars. These results suggest that Tead1 acts as a mediator of the biological functions of Yap, such as the morphogenesis of cusp formation, during tooth development.
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Affiliation(s)
- Yuki Niki
- Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan
| | - Yukiho Kobayashi
- Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan.
| | - Keiji Moriyama
- Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan
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38
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Hooglugt A, van der Stoel MM, Boon RA, Huveneers S. Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature. Front Oncol 2021; 10:612802. [PMID: 33614496 PMCID: PMC7890025 DOI: 10.3389/fonc.2020.612802] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/07/2020] [Indexed: 12/14/2022] Open
Abstract
Solid tumors are dependent on vascularization for their growth. The hypoxic, stiff, and pro-angiogenic tumor microenvironment induces angiogenesis, giving rise to an immature, proliferative, and permeable vasculature. The tumor vessels promote tumor metastasis and complicate delivery of anti-cancer therapies. In many types of tumors, YAP/TAZ activation is correlated with increased levels of angiogenesis. In addition, endothelial YAP/TAZ activation is important for the formation of new blood and lymphatic vessels during development. Oncogenic activation of YAP/TAZ in tumor cell growth and invasion has been studied in great detail, however the role of YAP/TAZ within the tumor endothelium remains insufficiently understood, which complicates therapeutic strategies aimed at targeting YAP/TAZ in cancer. Here, we overview the upstream signals from the tumor microenvironment that control endothelial YAP/TAZ activation and explore the role of their downstream targets in driving tumor angiogenesis. We further discuss the potential for anti-cancer treatments and vascular normalization strategies to improve tumor therapies.
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Affiliation(s)
- Aukie Hooglugt
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, Amsterdam, Netherlands
| | - Miesje M. van der Stoel
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Reinier A. Boon
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, Amsterdam, Netherlands
- German Center for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Berlin, Germany
- Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany
| | - Stephan Huveneers
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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39
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Zhuang Q, Li F, Liu J, Wang H, Tian Y, Zhang Z, Wang F, Zhao Z, Chen J, Wu H. Nuclear exclusion of YAP exacerbates podocyte apoptosis and disease progression in Adriamycin-induced focal segmental glomerulosclerosis. J Transl Med 2021; 101:258-270. [PMID: 33203894 PMCID: PMC7815513 DOI: 10.1038/s41374-020-00503-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 10/09/2020] [Accepted: 10/16/2020] [Indexed: 01/19/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a chronic glomerular disease with poor clinical outcomes. Podocyte loss via apoptosis is one important mechanism underlying the pathogenesis of FSGS. Recently, Yes-associated-protein (YAP), a key downstream protein in the Hippo pathway, was identified as an activator for multiple gene transcriptional factors in the nucleus to control cell proliferation and apoptosis. To investigate the potential role of YAP in the progression of FSGS, we examined kidney samples from patients with minimal change disease or FSGS and found that increases in podocyte apoptosis is positively correlated with the cytoplasmic distribution of YAP in human FSGS. Utilizing an established mT/mG transgenic mouse model and primary cultured podocytes, we found that YAP was distributed uniformly in nucleus and cytoplasm in the podocytes of control animals. Adriamycin treatment induced gradual nuclear exclusion of YAP with enhanced phospho-YAP/YAP ratio, accompanied by the induction of podocyte apoptosis both in vivo and in vitro. Moreover, we used verteporfin to treat an Adriamycin-induced FSGS mouse model, and found YAP inhibition by verteporfin induced nuclear exclusion of YAP, thus increasing podocyte apoptosis and accelerating disease progression. Therefore, our findings suggest that YAP nuclear distribution and activation in podocytes is an important endogenous anti-apoptotic mechanism during the progression of FSGS.
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Affiliation(s)
- Qiyuan Zhuang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Fang Li
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jun Liu
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongyu Wang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yuchen Tian
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhigang Zhang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Feng Wang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhonghua Zhao
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jianchun Chen
- Division of Nephrology in Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
| | - Huijuan Wu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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Xiu Z, Liu J, Wu X, Li X, Li S, Wu X, Lv X, Ye H, Tang X. Cytochalasin H isolated from mangrove-derived endophytic fungus inhibits epithelial-mesenchymal transition and cancer stemness via YAP/TAZ signaling pathway in non-small cell lung cancer cells. J Cancer 2021; 12:1169-1178. [PMID: 33442415 PMCID: PMC7797655 DOI: 10.7150/jca.50512] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 12/01/2020] [Indexed: 12/24/2022] Open
Abstract
Our previous studies have isolated cytochalasin H (CyH) from endophytic fungus derived from mangrove and found that CyH induced apoptosis and inhibited migration and angiogenesis in non-small cell lung cancer (NSCLC) cells. In this study, we further investigated the effect of CyH on epithelial-mesenchymal transition (EMT) and cancer stemness of A549 and NCI-H460 NSCLC cells and the underlying mechanisms, especially the role of YAP/ TAZ signaling pathway in the process. Our results showed that CyH significantly inhibited invasive ability and the sphere formation of NSCLC cells. The expression of E-cadherin, an EMT epithelial marker, was obviously up-regulated, while the expression of Vimentin and N-cadherin, the EMT mesenchymal markers, was dramatically down-regulated by CyH treatment in NSCLC cells. Moreover, the expression of EMT-associated transcription factors including Slug, Twist1, and Snail1 and stemness markers including Nanog, Sox-2, and Oct-4 was significantly down-regulated by CyH treatment in NSCLC cells. Additionally, CyH significantly down-regulated YAP and TAZ expression and up-regulated LAST1/2 and MST1/2 expression, and CyH inhibited the interaction between YAP and TEAD. Furthermore, YAP knockdown abolished the effect of CyH on the expression of EMT- and stemness-related markers in NSCLC cells. Taken together, these results suggest that CyH inhibits EMT and cancer stemness of NSCLC cells via the regulation of YAP/TAZ signaling pathway.
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Affiliation(s)
- Zihan Xiu
- Collaborative innovation center for antitumor active substance research and development, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Jiao Liu
- Collaborative innovation center for antitumor active substance research and development, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Xin Wu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Medical Research Institute of Guangdong Zhanjiang, Department of Pharmacology, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524023, P.R. China
| | - Xiangyong Li
- Collaborative innovation center for antitumor active substance research and development, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Sanzhong Li
- Collaborative innovation center for antitumor active substance research and development, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Xiaofeng Wu
- Collaborative innovation center for antitumor active substance research and development, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Xiaohua Lv
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Medical Research Institute of Guangdong Zhanjiang, Department of Pharmacology, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Hua Ye
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Medical Research Institute of Guangdong Zhanjiang, Department of Pharmacology, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524023, P.R. China
| | - Xudong Tang
- Collaborative innovation center for antitumor active substance research and development, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Medical Research Institute of Guangdong Zhanjiang, Department of Pharmacology, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524023, P.R. China.,Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Medical University, Dongguan 523808, P.R. China
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Jia J, Mo X, Yan F, Liu J, Ye S, Zhang Y, Lin Y, Li H, Chen D. Role of YAP-related T cell imbalance and epidermal keratinocyte dysfunction in the pathogenesis of atopic dermatitis. J Dermatol Sci 2020; 101:164-173. [PMID: 33358580 DOI: 10.1016/j.jdermsci.2020.12.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/16/2020] [Accepted: 12/16/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Atopic dermatitis (AD) is characterized by impaired skin barrier function and immune system dysfunction. The expression and role of Yes-associated protein (YAP) in AD are unclear. OBJECTIVE To characterize the role of the YAP in T cell imbalance and epidermal keratinocyte dysfunction in the pathogenesis of AD. METHODS We included 35 patients with AD (21 acute and 14 chronic). An AD mouse model was constructed using 2,4-dinitrofluorobenzene, and AD-like inflammatory cell model was constructed using TNF-α/IFN-γ-activated HaCaT cells. The proportion of Th1/Th2/Th17/Treg cells was detected using flow cytometry. After mononuclear cells were obtained from human peripheral blood or mouse spleen and induced to differentiate into different T cell subsets, YAP mRNA and protein expression were analyzed. Up-regulation of YAP was induced by lentivirus and down-regulation of YAP was induced by its specific inhibitor verteporfin (VP). The expression of YAP in skin lesions and infiltrating T cell subsets was detected using immunohistochemistry and double immunofluorescence staining, respectively. RESULTS We found differing degrees of Th1/Th2/Th17/Treg imbalance in acute and chronic AD. YAP expression was downregulated in Treg cells and upregulated in Th17 cells; YAP expression was downregulated in the AD epidermis. After YAP overexpression, the proportion of both Th17 and the Treg cells differentiated from mouse spleen mononuclear cells increased. There was an opposite trend after YAP inhibition. The proliferation and migration decreased and apoptosis increased after YAP inhibition in HaCaT cells. CONCLUSION Change of YAP expression may cause T cell imbalance and hamper the healing of the epidermis in AD.
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Affiliation(s)
- Jinjing Jia
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China
| | - Xiumei Mo
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China
| | - Fenggen Yan
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China
| | - Junfeng Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China
| | - Siqi Ye
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China
| | - Yu Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China
| | - Ying Lin
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China
| | - Hongyi Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China
| | - Dacan Chen
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, China.
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Kunig VBK, Potowski M, Akbarzadeh M, Klika Škopić M, dos Santos Smith D, Arendt L, Dormuth I, Adihou H, Andlovic B, Karatas H, Shaabani S, Zarganes‐Tzitzikas T, Neochoritis CG, Zhang R, Groves M, Guéret SM, Ottmann C, Rahnenführer J, Fried R, Dömling A, Brunschweiger A. TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics. Angew Chem Int Ed Engl 2020; 59:20338-20342. [PMID: 32537835 PMCID: PMC7689693 DOI: 10.1002/anie.202006280] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/20/2020] [Indexed: 01/12/2023]
Abstract
DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or "hot spot", regions of protein-protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide "hexT", encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.
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Affiliation(s)
- Verena B. K. Kunig
- TU Dortmund UniversityFaculty of Chemistry and Chemical BiologyOtto-Hahn-Strasse 644227DortmundGermany
| | - Marco Potowski
- TU Dortmund UniversityFaculty of Chemistry and Chemical BiologyOtto-Hahn-Strasse 644227DortmundGermany
| | - Mohammad Akbarzadeh
- Max Planck Institute of Molecular PhysiologyDepartment of Chemical BiologyOtto-Hahn-Strasse 1144227DortmundGermany
| | - Mateja Klika Škopić
- TU Dortmund UniversityFaculty of Chemistry and Chemical BiologyOtto-Hahn-Strasse 644227DortmundGermany
| | - Denise dos Santos Smith
- TU Dortmund UniversityFaculty of Chemistry and Chemical BiologyOtto-Hahn-Strasse 644227DortmundGermany
| | - Lukas Arendt
- TU Dortmund UniversityFaculty of StatisticsVogelpothsweg 8744227DortmundGermany
| | - Ina Dormuth
- TU Dortmund UniversityFaculty of StatisticsVogelpothsweg 8744227DortmundGermany
| | - Hélène Adihou
- Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM)BioPharmaceuticals R&DAstraZeneca43150GothenburgSweden
- AstraZeneca-Max Planck Institute Satellite UnitMax-Planck Institute of Molecular PhysiologyDepartment of Chemical BiologyOtto-Hahn-Strasse 1144227DortmundGermany
| | - Blaž Andlovic
- Lead Discovery Center GmbH (Germany)Otto-Hahn-Strasse 1544227DortmundGermany
- Laboratory of Chemical BiologyDepartment of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyDen Dolech 25612AZEindhovenThe Netherlands
| | - Hacer Karatas
- Max Planck Institute of Molecular PhysiologyDepartment of Chemical BiologyOtto-Hahn-Strasse 1144227DortmundGermany
| | - Shabnam Shaabani
- University of GroningenDrug DesignDeusinglaan 17313AVGroningenThe Netherlands
| | | | - Constantinos G. Neochoritis
- University of GroningenDrug DesignDeusinglaan 17313AVGroningenThe Netherlands
- University of CreteDepartment of Chemistry70013HeraklionGreece
| | - Ran Zhang
- University of GroningenDrug DesignDeusinglaan 17313AVGroningenThe Netherlands
| | - Matthew Groves
- University of GroningenDrug DesignDeusinglaan 17313AVGroningenThe Netherlands
| | - Stéphanie M. Guéret
- Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM)BioPharmaceuticals R&DAstraZeneca43150GothenburgSweden
- AstraZeneca-Max Planck Institute Satellite UnitMax-Planck Institute of Molecular PhysiologyDepartment of Chemical BiologyOtto-Hahn-Strasse 1144227DortmundGermany
| | - Christian Ottmann
- Laboratory of Chemical BiologyDepartment of Biomedical Engineering and Institute for Complex Molecular SystemsEindhoven University of TechnologyDen Dolech 25612AZEindhovenThe Netherlands
| | - Jörg Rahnenführer
- TU Dortmund UniversityFaculty of StatisticsVogelpothsweg 8744227DortmundGermany
| | - Roland Fried
- TU Dortmund UniversityFaculty of StatisticsVogelpothsweg 8744227DortmundGermany
| | - Alexander Dömling
- University of GroningenDrug DesignDeusinglaan 17313AVGroningenThe Netherlands
| | - Andreas Brunschweiger
- TU Dortmund UniversityFaculty of Chemistry and Chemical BiologyOtto-Hahn-Strasse 644227DortmundGermany
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Mesrouze Y, Bokhovchuk F, Meyerhofer M, Zimmermann C, Fontana P, Erdmann D, Chène P. Study of the TEAD-binding domain of the YAP protein from animal species. Protein Sci 2020; 30:339-349. [PMID: 33146905 PMCID: PMC7784741 DOI: 10.1002/pro.3988] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/18/2020] [Accepted: 10/30/2020] [Indexed: 11/30/2022]
Abstract
The Hippo signaling pathway, which plays a central role in the control of organ size in animals, is well conserved in metazoans. The most downstream elements of this pathway are the TEAD transcription factors that are regulated by their association with the transcriptional coactivator YAP. Therefore, the creation of the binding interface that ensures the formation of the YAP:TEAD complex is a critical molecular recognition event essential for the development/survival of many living organisms. In this report, using the available structural information on the YAP:TEAD complex, we study the TEAD‐binding domain of YAP from different animal species. This analysis of more than 400 amino acid sequences reveals that the residues from YAP involved in the formation of the two main contact regions with TEAD are very well conserved. Therefore, the binding interface between YAP and TEAD, as found in humans, probably appeared at an early evolutionary stage in metazoans. We find that, in contrast to most other animal species, several Actinopterygii species possess YAP variants with a different TEAD‐binding domain. However, these variants bind to TEAD with a similar affinity. Our studies show that the protein identified as a YAP homolog in Caenorhabditis elegans does not contain the TEAD‐binding domain found in YAP of other metazoans. Finally, we do not identify in non‐metazoan species, amino acid sequences containing both a TEAD‐binding domain, as in metazoan YAP, and WW domain(s).
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Affiliation(s)
- Yannick Mesrouze
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Fedir Bokhovchuk
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Marco Meyerhofer
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Catherine Zimmermann
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Patrizia Fontana
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Dirk Erdmann
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Patrick Chène
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
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Zhang D, He D, Pan X, Liu L. Rational Design and Intramolecular Cyclization of Hotspot Peptide Segments at YAP–TEAD4 Complex Interface. Protein Pept Lett 2020; 27:999-1006. [DOI: 10.2174/0929866527666200414160723] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/13/2020] [Accepted: 02/24/2020] [Indexed: 11/22/2022]
Abstract
Background:
The Yes-Associated Protein (YAP) is a central regulator of Hippo pathway
involved in carcinogenesis, which functions through interaction with TEA Domain (TEAD)
transcription factors. Pharmacological disruption of YAP–TEAD4 complexes has been recognized
as a potential therapeutic strategy against diverse cancers by suppressing the oncogenic activity of
YAP.
Objective:
Two peptides, termed PS-1 and PS-2 are split from the interfacial context of YAP protein.
Dynamics simulations, energetics analyses and fluorescence polarizations are employed to
characterize the intrinsic disorder as well as binding energy/affinity of the two YAP peptides to
TEAD4 protein.
Methods:
Two peptides, termed PS-1 and PS-2 are split from the interfacial context of YAP protein.
Dynamics simulations, energetics analyses and fluorescence polarizations are employed to
characterize the intrinsic disorder as well as binding energy/affinity of the two YAP peptides to
TEAD4 protein.
Result:
The native conformation of PS-2 peptide is a cyclic loop, which is supposed to be constrained
by adding a disulfide bond across the spatially vicinal residue pair Arg87-Phe96 or Met86-
Phe95 at the peptide’s two ends, consequently resulting in two intramolecular cyclized counterparts
of linear PS-2 peptide, namely PS-2(cyc87,96) and PS-2(cyc86,95). The linear PS-2 peptide
is determined as a weak binder of TEAD4 (Kd = 190 μM), while the two cyclic PS-2(cyc87,96) and
PS-2(cyc86,95) peptides are measured to have moderate or high affinity towards TEAD4 (Kd = 21
and 45 μM, respectively).
Conclusion:
PS-1 and PS-2 peptides are highly flexible and cannot maintain in native active conformation
when splitting from the interfacial context, and thus would incur a considerable entropy
penalty upon rebinding to the interface. Cyclization does not influence the direct interaction between
PS-2 peptide and TEAD4 protein, but can largely reduce the intrinsic disorder of PS-2 peptide
in free state and considerably minimize indirect entropy effect upon the peptide binding.
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Affiliation(s)
- Dingwa Zhang
- School of Chemistry and Chemical Engineering, Jinggangshan University, Ji’an 343009, China
| | - Deyong He
- School of Chemistry and Chemical Engineering, Jinggangshan University, Ji’an 343009, China
| | - Xiaoliang Pan
- School of Mechanical and Electrical Engineering, Jinggangshan University, Ji’an 343009, China
| | - Lijun Liu
- School of Chemistry and Chemical Engineering, Jinggangshan University, Ji’an 343009, China
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Wei C, Li X. Determination of the migration effect and molecular docking of verteporfin in different subtypes of breast cancer cells. Mol Med Rep 2020; 22:3955-3961. [PMID: 32901856 PMCID: PMC7533488 DOI: 10.3892/mmr.2020.11482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 07/28/2020] [Indexed: 12/17/2022] Open
Abstract
Breast cancer is one of the most aggressive malignant tumors in women. According to the expression differences of estrogen receptor, progesterone receptor, human epidermal growth factor receptor‑2 (HER‑2) and cell proliferation antigen Ki‑67, breast cancer can be divided into four molecular subtypes: Luminal A, Luminal B, HER‑2 overexpression and Basal‑like. Yes‑associated protein (YAP), a downstream effector of the Hippo pathway, is overexpressed in human cancers and is associated with proliferation, apoptosis, migration, invasion and resistance to chemotherapy drugs in breast cancer cells. Verteporfin (VP) is used as a photosensitizer in the treatment of neovascular macular degeneration. VP is also identified as an inhibitor of YAP/TEA domain transcription factor (TEAD) interaction in the absence of light activation. However, detailed structural information about VP and YAP interactions is relatively scarce and VP research targeting YAP in different molecular subtypes of breast cancer cells is also rare. The aims of the present study were to structurally describe the VP binding site in the YAP crystal structure and to verify the non‑photoreactive VP effect targeting YAP on the migration of different molecular subtypes of breast cancer cells. The crystal structure of VP and YAP was calculated by AutoDock 4.2 and the result was illustrated using PyMOL. The non‑photoactivated VP effect on the migration of Luminal A MCF‑7, Luminal B BT‑474 and triple‑negative breast cancer BT‑549 breast cancer cells was evaluated by wound healing and Transwell migration experiments. Results from molecular docking experiments demonstrated that VP could interact through hydrogen bonds and hydrophobic interactions with important YAP residues involved in TEADs binding (Gln82, Val84, Met86 and Arg89). Migration experiments revealed that the non‑photoinduced VP could inhibit the migration of different molecular subtypes of breast cancer cells. The results of the present study indicated that VP may be a novel repositioned drug for breast cancer treatment in the future.
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Affiliation(s)
- Changran Wei
- Department of The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Xiangqi Li
- Department of The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
- Department of Breast Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, Shandong 271000, P.R. China
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Wei C, Li X. The Role of Photoactivated and Non-Photoactivated Verteporfin on Tumor. Front Pharmacol 2020; 11:557429. [PMID: 33178014 PMCID: PMC7593515 DOI: 10.3389/fphar.2020.557429] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/18/2020] [Indexed: 12/11/2022] Open
Abstract
Verteporfin (VP) has long been clinically used to treat age-related macular degeneration (AMD) through photodynamic therapy (PDT). Recent studies have reported a significant anti-tumor effect of VP as well. Yes-associated protein (YAP) is a pro-tumorigenic factor that is aberrantly expressed in various cancers and is a central effector of the Hippo signaling pathway that regulates organ size and tumorigenesis. VP can inhibit YAP without photoactivation, along with suppressing autophagy, and downregulating germinal center kinase-like kinase (GLK) and STE20/SPS1-related proline/alanine-rich kinase (SPAK). In addition, VP can induce mitochondrial damage and increase the production of reactive oxygen species (ROS) upon photoactivation, and is an effective photosensitizer (PS) in anti-tumor PDT. We have reviewed the direct and adjuvant therapeutic action of VP as a PS, and its YAP/TEA domain (TEAD)-dependent and independent pharmacological effects in the absence of light activation against cancer cells and solid tumors. Based on the present evidence, VP may be repositioned as a promising anti-cancer chemotherapeutic and adjuvant drug.
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Affiliation(s)
- Changran Wei
- Department of The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiangqi Li
- Department of The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
- Department of Breast Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai’an, China
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A new perspective on the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors. Sci Rep 2020; 10:17442. [PMID: 33060790 PMCID: PMC7566471 DOI: 10.1038/s41598-020-74584-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023] Open
Abstract
The most downstream elements of the Hippo pathway, the TEAD transcription factors, are regulated by several cofactors, such as Vg/VGLL1-3. Earlier findings on human VGLL1 and here on human VGLL3 show that these proteins interact with TEAD via a conserved amino acid motif called the TONDU domain. Surprisingly, our studies reveal that the TEAD-binding domain of Drosophila Vg and of human VGLL2 is more complex and contains an additional structural element, an Ω-loop, that contributes to TEAD binding. To explain this unexpected structural difference between proteins from the same family, we propose that, after the genome-wide duplications at the origin of vertebrates, the Ω-loop present in an ancestral VGLL gene has been lost in some VGLL variants. These findings illustrate how structural and functional constraints can guide the evolution of transcriptional cofactors to preserve their ability to compete with other cofactors for binding to transcription factors.
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Astamal RV, Maghoul A, Taefehshokr S, Bagheri T, Mikaeili E, Derakhshani A, Delashoub M, Taefehshokr N, Isazadeh A, Hajazimian S, Tran A, Baradaran B. Regulatory role of microRNAs in cancer through Hippo signaling pathway. Pathol Res Pract 2020; 216:153241. [PMID: 33065484 DOI: 10.1016/j.prp.2020.153241] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/29/2020] [Accepted: 10/04/2020] [Indexed: 12/18/2022]
Abstract
Cancer is the major cause of death worldwide in countries of all income levels. The Hippo signaling pathway is a Drosophila kinase gene that was identified to regulate organ size, cell regeneration, and contribute to tumorigenesis. A huge variety of extrinsic and intrinsic signals regulate the Hippo signaling pathway. The Hippo signaling pathway consists of a wide array of components that merge numerous signals such as mechanical signals to address apoptosis resistance, cell proliferation, cellular outputs of growth, cell death and survival at cellular and tissue level. Recent studies have shed new light on the regulatory role of microRNAs in Hippo signaling and how they contribute to cancer progression. MicroRNAs influence various cancer-related processes such as, apoptosis, proliferation, migration, cell cycle and metabolism. Inhibition and overexpression of miRNAs via miRNA mimics and miRNA inhibitors, respectively, can uncover a hopeful and reliable insight for treatment and early diagnosis of cancer patients. In this review we will discuss our current understanding of regulatory role of miRNAs in Hippo signaling pathway.
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Affiliation(s)
- Reza Vaezi Astamal
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Biotechnology Research Center, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Asma Maghoul
- Biotechnology Research Center, Tabriz Branch, Islamic Azad University, Tabriz, Iran; Department of Basic Sciences, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Sina Taefehshokr
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Taha Bagheri
- Department of Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Ehsan Mikaeili
- Department of Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masoud Delashoub
- Biotechnology Research Center, Tabriz Branch, Islamic Azad University, Tabriz, Iran; Department of Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran.
| | - Nima Taefehshokr
- Department of Microbiology and Immunology, Center for Human Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Alireza Isazadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Hajazimian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Antalique Tran
- Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT, 06536, USA
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Karatas H, Akbarzadeh M, Adihou H, Hahne G, Pobbati AV, Yihui Ng E, Guéret SM, Sievers S, Pahl A, Metz M, Zinken S, Dötsch L, Nowak C, Thavam S, Friese A, Kang C, Hong W, Waldmann H. Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain Central Pocket. J Med Chem 2020; 63:11972-11989. [PMID: 32907324 PMCID: PMC7586386 DOI: 10.1021/acs.jmedchem.0c01275] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
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Transcriptional enhanced associate
domain (TEAD) transcription
factors together with coactivators and corepressors modulate the expression
of genes that regulate fundamental processes, such as organogenesis
and cell growth, and elevated TEAD activity is associated with tumorigenesis.
Hence, novel modulators of TEAD and methods for their identification
are in high demand. We describe the development of a new “thiol
conjugation assay” for identification of novel small molecules
that bind to the TEAD central pocket. The assay monitors prevention
of covalent binding of a fluorescence turn-on probe to a cysteine
in the central pocket by small molecules. Screening of a collection
of compounds revealed kojic acid analogues as TEAD inhibitors, which
covalently target the cysteine in the central pocket, block the interaction
with coactivator yes-associated protein with nanomolar apparent IC50 values, and reduce TEAD target gene expression. This methodology
promises to enable new medicinal chemistry programs aimed at the modulation
of TEAD activity.
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Affiliation(s)
- Hacer Karatas
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - Mohammad Akbarzadeh
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - Hélène Adihou
- Department of Chemical Biology, AstraZeneca-Max Planck Institute Satellite Unit, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.,Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, SE-431 83 Gothenburg, Sweden
| | - Gernot Hahne
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - Ajaybabu V Pobbati
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, 138673 Singapore, Singapore
| | - Elizabeth Yihui Ng
- Experimental Drug Development Centre (EDDC), Agency for Science, Technology and Research (A*STAR), 10 Biopolis Road, Chromos, #05-01, 138670, Singapore
| | - Stéphanie M Guéret
- Department of Chemical Biology, AstraZeneca-Max Planck Institute Satellite Unit, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.,Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, SE-431 83 Gothenburg, Sweden
| | - Sonja Sievers
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - Axel Pahl
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - Malte Metz
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - Sarah Zinken
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany.,Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany
| | - Lara Dötsch
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany.,Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany
| | - Christine Nowak
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - Sasikala Thavam
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - Alexandra Friese
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany
| | - CongBao Kang
- Experimental Drug Development Centre (EDDC), Agency for Science, Technology and Research (A*STAR), 10 Biopolis Road, Chromos, #05-01, 138670, Singapore
| | - Wanjin Hong
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, 138673 Singapore, Singapore
| | - Herbert Waldmann
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany.,Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany
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50
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Jiang L, Li J, Zhang C, Shang Y, Lin J. YAP‑mediated crosstalk between the Wnt and Hippo signaling pathways (Review). Mol Med Rep 2020; 22:4101-4106. [PMID: 33000236 DOI: 10.3892/mmr.2020.11529] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 08/18/2020] [Indexed: 11/06/2022] Open
Abstract
Yes‑associated protein (YAP) acts as a transcriptional co‑activator in gene expression and cell proliferation control by binding to the transcriptional factor TEA domain (TEAD) of the Hippo signaling pathway in the nucleus, and also acts as a regulator by binding to another transcriptional co‑activator, β‑catenin of the Wnt signaling pathway. Whether YAP preferentially acts as a transcriptional co‑regulator of the activity of the Hippo signaling pathway or as a regulator in the Wnt signaling pathway depends on the cell type. Nuclear YAP upregulates the expression of β‑catenin, while cytoplasmic YAP has a negative effect on this expression. The present mini‑review focused on the important roles of YAP and further discussed the cross‑links between the Wnt and Hippo signaling pathways. The Wnt and Hippo signaling pathways are both related to the development of fibrosis or cancer. The current review discussed treatment approaches for these conditions based on the two pathways. YAP, the intersection of these two signaling pathways, has the potential to be developed as a novel treatment target, according to previous basic studies on fibroblasts and cancer cells.
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Affiliation(s)
- Liya Jiang
- Department of Stomatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Juan Li
- Department of Stomatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Chenxing Zhang
- Department of Stomatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Yufeng Shang
- Department of Stomatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Jun Lin
- Department of Stomatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
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