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Chuang LSH, Ito Y. The Multiple Interactions of RUNX with the Hippo-YAP Pathway. Cells 2021; 10:2925. [PMID: 34831147 PMCID: PMC8616315 DOI: 10.3390/cells10112925] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 01/04/2023] Open
Abstract
The Hippo-YAP signaling pathway serves roles in cell proliferation, stem cell renewal/maintenance, differentiation and apoptosis. Many of its functions are central to early development, adult tissue repair/regeneration and not surprisingly, tumorigenesis and metastasis. The Hippo pathway represses the activity of YAP and paralog TAZ by modulating cell proliferation and promoting differentiation to maintain tissue homeostasis and proper organ size. Similarly, master regulators of development RUNX transcription factors have been shown to play critical roles in proliferation, differentiation, apoptosis and cell fate determination. In this review, we discuss the multiple interactions of RUNX with the Hippo-YAP pathway, their shared collaborators in Wnt, TGFβ, MYC and RB pathways, and their overlapping functions in development and tumorigenesis.
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Affiliation(s)
| | - Yoshiaki Ito
- NUS Centre for Cancer Research, Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore
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Gao L, Zhou F. Comprehensive Analysis of RUNX and TGF-β Mediated Regulation of Immune Cell Infiltration in Breast Cancer. Front Cell Dev Biol 2021; 9:730380. [PMID: 34485309 PMCID: PMC8416425 DOI: 10.3389/fcell.2021.730380] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 07/28/2021] [Indexed: 01/05/2023] Open
Abstract
Runt-related transcription factors (RUNXs) can serve as both transcription activators and repressors during biological development, including immune cell maturation. RUNX factors have both tumor-promoting and tumor-suppressive roles in carcinogenesis. Immune cell infiltration and the tumor immune microenvironment have been found to be key regulators in breast cancer progression, treatment response, and patient outcome. However, the relationship between the RUNX family and immune cell infiltration in breast cancer remains unclear. We performed a comprehensive analysis to reveal the role of RUNX factors in breast cancer. Analysis of patient data in the Oncomine database showed that the transcriptional levels of RUNX proteins in breast cancer were elevated. Kaplan–Meier plotter (KM plotter) analysis showed that breast cancer patients with higher expression of RUNX proteins had better survival outcomes. Through analysis of the UALCAN database, we found that the transcriptional levels of RUNX factors were significantly correlated with some breast cancer patient characteristics. cBio Cancer Genomics Portal (cBioPortal) analysis showed the proportions of different RUNX genomic alterations in various subclasses of breast cancer. We also performed gene ontology (GO) and pathway analyses for the significantly differentially expressed genes that were correlated with RUNX factors in breast cancer. TIMER database analysis showed that immune cell infiltration in breast cancer could be affected by the transcriptional level, mutation, and gene copy number of RUNX proteins. Using the Gene Set Cancer Analysis (GSCA) database, we analyzed the effects of RUNX gene methylation on the level of immune cell infiltration in breast cancer. We found that the methylation level changes of RUNX2 and RUNX3 had opposite effects on immune cell infiltration in breast cancer. We also analyzed the relationship between the methylation level of RUNX genes and the TGF-β signaling pathway using the TISIDB database. The results showed that the methylation levels of RUNX1 and RUNX3 were correlated with the expression of TGF-β1. In summary, our analysis found that the RUNX family members can influence the infiltration of various immune cells in breast cancer depending on their expression level, mutation, gene copy number, and methylation. The RUNX family is an important regulator of immune cell infiltration in breast cancer and may serve as a potential prognostic biomarker.
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Affiliation(s)
- Liang Gao
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Fangfang Zhou
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
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3
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A WW Tandem-Mediated Dimerization Mode of SAV1 Essential for Hippo Signaling. Cell Rep 2021; 32:108118. [PMID: 32905778 PMCID: PMC7494017 DOI: 10.1016/j.celrep.2020.108118] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/27/2020] [Accepted: 08/17/2020] [Indexed: 12/11/2022] Open
Abstract
The canonical mammalian Hippo pathway contains a core kinase signaling cascade requiring upstream MST to form a stable complex with SAV1 in order to phosphorylate the downstream LATS/MOB complex. Though SAV1 dimerization is essential for the trans-activation of MST, the molecular mechanism underlying SAV1 dimerization is unclear. Here, we discover that the SAV1 WW tandem containing a short Pro-rich extension immediately following the WW tandem (termed as "WW12ex") forms a highly stable homodimer. The crystal structure of SAV1 WW12ex reveals that the Pro-rich extension of one subunit binds to both WW domains from the other subunit. Thus, SAV1 WW12ex forms a domain-swapped dimer instead of a WW2 homodimerization-mediated dimer. The WW12ex-mediated dimerization of SAV1 is required for the MST/SAV1 complex assembly and MST kinase activation. Finally, we show that several cancer-related SAV1 variants disrupt SAV1 dimer formation, and thus, these mutations may impair the tumor-suppression activity of SAV1.
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The tumor suppressor role of salvador family WW domain-containing protein 1 (SAV1): one of the key pieces of the tumor puzzle. J Cancer Res Clin Oncol 2021; 147:1287-1297. [PMID: 33580421 DOI: 10.1007/s00432-021-03552-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/04/2021] [Indexed: 10/22/2022]
Abstract
PURPOSE In the complex tumor scenario, understanding the function of proteins with protumor or antitumor roles is essential to support advances in the cancer clinical area. Among them, the salvador family WW domain-containing protein 1 (SAV1) is highlighted. This protein plays a fundamental role in the tumor suppressor face of the Hippo pathway, which are responsible for controlling cell proliferation, organ size, development and tissue homeostasis. However, the functional dysregulation of this pathway may contribute to tumorigenesis and tumor progression. As SAV1 is a tumor suppressor scaffold protein, we explored the functions performed by SAV1 with its partners, the regulation of its expression, and its antitumor role in various types of cancer. METHODS We selected and analyzed 80 original articles and reviews from Pubmed that focuses on the study of SAV1 in cancer. RESULTS SAV1 interacts with several proteins, has different functions and acts as tumor suppressor by other mechanisms besides Hippo pathway. SAV1 expression regulation seems to occur by microRNAs and rarely by mutation or promoter methylation. It is downregulated in different types of cancer, which leads to cancer promotion and progression and is associated with poor prognosis. In vivo models have shown that the loss of SAV1 contributes to tumorigenesis. CONCLUSION SAV1 plays a relevant role as tumor suppressor in several types of cancer, highlighting SAV1 and the Hippo pathway's importance to cancer. Thus, encouraging further studies to include the SAV1 as a molecular key piece in cancer biology and in clinical approaches to cancer.
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Xie S, Chang Y, Jin H, Yang F, Xu Y, Yan X, Lin A, Shu Q, Zhou T. Non-coding RNAs in gastric cancer. Cancer Lett 2020; 493:55-70. [PMID: 32712234 DOI: 10.1016/j.canlet.2020.06.022] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/19/2020] [Accepted: 06/28/2020] [Indexed: 12/11/2022]
Abstract
Non-coding RNAs (ncRNAs) are functional RNA molecules that play crucial regulatory roles in many fundamental biological processes. The dysregulation of ncRNAs is significantly associated with the progression of human cancers, including gastric cancer. In this review, we have summarized the oncogenic or tumor-suppressive roles and the regulatory mechanisms of lncRNAs, miRNAs, circRNAs and piRNAs, and have discussed their potential as biomarkers or therapeutic targets in gastric cancer.
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Affiliation(s)
- Shanshan Xie
- The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China; Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yongxia Chang
- Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China
| | - Hao Jin
- Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China
| | - Feng Yang
- Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China
| | - Yanjun Xu
- Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Xiaoyi Yan
- Cancer Center, Zhejiang University, Hangzhou, 310058, China
| | - Aifu Lin
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Qiang Shu
- The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China.
| | - Tianhua Zhou
- Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
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6
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Won GW, Sung M, Lee Y, Lee YH. MST2 kinase regulates osteoblast differentiation by phosphorylating and inhibiting Runx2 in C2C12 cells. Biochem Biophys Res Commun 2019; 512:591-597. [DOI: 10.1016/j.bbrc.2019.03.097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 03/16/2019] [Indexed: 01/19/2023]
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RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway. J Neurooncol 2018; 140:15-26. [PMID: 29916101 DOI: 10.1007/s11060-018-2927-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 06/09/2018] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Runt-related transcription factor 3 (RUNX3) exerts a tumor suppressor gene associated with gastric and other cancers, including glioma. However, how its anti-tumor mechanism in functions glioma is unclear. METHODS We assayed expression of RUNX3 with a tissue microarray (TMA), frozen cancer tissues and malignant glioma cell lines using immunohistochemistry, qRT-PCR and Western bolt analysis. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm the effect of RUNX3 medicated malignant phenotype. TOP/FOP experiment was used to detect the β-catenin/Tcf-4 transcription activity by RUNX3. RESULTS Enforced RUNX3 expression inhibited proliferation and invasion, induced cell cycle arrest and promoted apoptosis in vitro and in vivo, Bim siRNA partically reversed the effect of RUNX3-induced apoptosis in LN229 and U87 cells, suggesting a dependent role of Bim-caspase pathway. Moreover, Mechanism investigations revealed that restoration of RUNX3 suppressed β-catenin/Tcf-4 transcription activity. CONCLUSIONS RUNX3 plays a pivotal role in glioma initiation and progression as a tumor suppressor via attenuation of Wnt signaling, highlighting it as a potential therapeutic target for glioma.
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Xu J, Zhu X, Li Q, Chen C, Guo Z, Tan Z, Zheng C, Ge M. Loss of PIM1 correlates with progression and prognosis of salivary adenoid cystic carcinoma (SACC). Cancer Cell Int 2018; 18:22. [PMID: 29467592 PMCID: PMC5819291 DOI: 10.1186/s12935-018-0518-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 02/03/2018] [Indexed: 12/31/2022] Open
Abstract
Background Increasing evidence indicates that PIM1 is a potential prognostic marker and target for cancer treatment but its precise mechanisms of action remain to be determined in salivary adenoid cystic carcinoma (SACC). This study aims to decipher the prognostic and mechanistic role of PIM1 in progression of SACC cells and tumor tissues. Methods A SACC cell line (ACC-M) was transfected with shRNA plasmids targeting the PIM1 gene. The expression levels of PIM1, RUNX3 and p21 were measured by quantitative real-time PCR and western blot. Subcellular translocalization of RUNX3 and p21 proteins was assessed using immunofluorescence, and cell cycle phase was quantified using flow cytometry. A total of 97 SACC patients were retrospectively analyzed by clinicopathologic characteristics and survival outcomes. Results After down-regulation of PIM1 in ACC-M cells, RUNX3 and p21 proteins were translocated from cytoplasm to nucleus, with a decrease of p21 expression and increase of G0/G1 phase cells. PIM1 and RUNX3 levels show a distinct covariance. PIM1 is associated with T-status, lymph node involvement, nerve invasion, and distant metastasis in SACC tissues. Patients with low PIM1 level had a better outcome than those with higher PIM1 level. Conclusions PIM1 is multifunctional in ACC-M cells and it serves as a neoteric therapeutic target and potential prognostic marker for SACC patients.
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Affiliation(s)
- Jiajie Xu
- 1Department of Head and Neck Surgery, Zhejiang Cancer Hospital, No. 38 Guangji Road, Hangzhou, 310022 Zhejiang China
| | - Xin Zhu
- 2Zhejiang Cancer Research Institute, Hangzhou, 310022 China
| | - Qingling Li
- 3Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022 China
| | - Chao Chen
- 1Department of Head and Neck Surgery, Zhejiang Cancer Hospital, No. 38 Guangji Road, Hangzhou, 310022 Zhejiang China
| | - Zhenying Guo
- 4Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, 310022 China
| | - Zhuo Tan
- 1Department of Head and Neck Surgery, Zhejiang Cancer Hospital, No. 38 Guangji Road, Hangzhou, 310022 Zhejiang China
| | - Chuanming Zheng
- 1Department of Head and Neck Surgery, Zhejiang Cancer Hospital, No. 38 Guangji Road, Hangzhou, 310022 Zhejiang China
| | - Minghua Ge
- 1Department of Head and Neck Surgery, Zhejiang Cancer Hospital, No. 38 Guangji Road, Hangzhou, 310022 Zhejiang China
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Xia J, Zeng M, Zhu H, Chen X, Weng Z, Li S. Emerging role of Hippo signalling pathway in bladder cancer. J Cell Mol Med 2017; 22:4-15. [PMID: 28782275 PMCID: PMC5742740 DOI: 10.1111/jcmm.13293] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 05/31/2017] [Indexed: 12/22/2022] Open
Abstract
Bladder cancer (BC) is one of the most common cancers worldwide with a high progression rate and poor prognosis. The Hippo signalling pathway is a conserved pathway that plays a crucial role in cellular proliferation, differentiation and apoptosis. Furthermore, dysregulation and/or malfunction of the Hippo pathway is common in various human tumours, including BC. In this review, an overview of the Hippo pathway in BC and other cancers is presented. We focus on recent data regarding the Hippo pathway, its network and the regulation of the downstream co-effectors YAP1/TAZ. The core components of the Hippo pathway, which induce BC stemness acquisition, metastasis and chemoresistance, will be emphasized. Additional research on the Hippo pathway will advance our understanding of the mechanism of BC as well as the development and progression of other cancers and may be exploited therapeutically.
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Affiliation(s)
- Jianling Xia
- Cancer Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Hospital of the University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Ming Zeng
- Cancer Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Hospital of the University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Hua Zhu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangjian Chen
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhiliang Weng
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shi Li
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Runx3 and Cell Fate Decisions in Pancreas Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 962:333-352. [PMID: 28299667 DOI: 10.1007/978-981-10-3233-2_21] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The RUNX family transcription factors are critical regulators of development and frequently dysregulated in cancer. RUNX3, the least well characterized of the three family members, has been variously described as a tumor promoter or suppressor, sometimes with conflicting results and opinions in the same cancer and likely reflecting a complex role in oncogenesis. We recently identified RUNX3 expression as a crucial determinant of the predilection for pancreatic ductal adenocarcinoma (PDA) cells to proliferate locally or promulgate throughout the body. High RUNX3 expression induces the production and secretion of soluble factors that support metastatic niche construction and stimulates PDA cells to migrate and invade, while simultaneously suppressing proliferation through increased expression of cell cycle regulators such as CDKN1A/p21 WAF1/CIP1 . RUNX3 expression and function are coordinated by numerous transcriptional and post-translational inputs, and interactions with diverse cofactors influence whether the resulting RUNX3 complexes enact tumor suppressive or tumor promoting programs. Understanding these exquisitely context-dependent tumor cell behaviors has the potential to inform clinical decision-making including the most appropriate timing and sequencing of local vs. systemic therapies.
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11
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Passaniti A, Brusgard JL, Qiao Y, Sudol M, Finch-Edmondson M. Roles of RUNX in Hippo Pathway Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 962:435-448. [PMID: 28299672 DOI: 10.1007/978-981-10-3233-2_26] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The Runt-domain (RD) transcription factors (RUNX genes) are an important family of transcriptional mediators that interact with a variety of proteins including the Hippo pathway effector proteins, YAP and TAZ. In this chapter we focus on two examples of RUNX-TAZ/YAP interactions that have particular significance in human cancer. Specifically, recent evidence has found that RUNX2 cooperates with TAZ to promote epithelial to mesenchymal transition mediated by the soluble N-terminal ectodomain of E-Cadherin, sE-Cad. Contrastingly, in gastric cancer, RUNX3 acts as a tumor suppressor via inhibition of the YAP-TEAD complex and disruption of downstream YAP-mediated gene transcription and the oncogenic phenotype. The reports highlighted in this chapter add to the growing repertoire of instances of Hippo pathway crosstalk that have been identified in cancer. Elucidation of these increasingly complex interactions may help to identify novel strategies to target Hippo pathway dysregulation in human cancer.
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Affiliation(s)
- Antonino Passaniti
- Department of Pathology and Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, and the Veterans Administration Health Service, Baltimore, MD, USA.
| | - Jessica L Brusgard
- Department of Pathology and Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, and the Veterans Administration Health Service, Baltimore, MD, USA
| | - Yiting Qiao
- The Mechanobiology Institute (MBI) and the NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
| | - Marius Sudol
- The Mechanobiology Institute (MBI) and the NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
- Institute of Molecular and Cell Biology A*STAR, Singapore, Republic of Singapore
| | - Megan Finch-Edmondson
- The Mechanobiology Institute (MBI) and the NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
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Abstract
The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1-6 and Sav1/WW45. Early studies emphasized the potent ability of MST1/MST2 to induce apoptosis upon being overexpressed, as well as the conversion of the endogenous MST1/MST2 polypeptides to constitutively active, caspase-cleaved catalytic fragments during apoptosis initiated by any stimulus. Later, the cleaved, constitutively active form of MST1 was identified in nonapoptotic, quiescent adult hepatocytes as well as in cells undergoing terminal differentiation, where its presence is necessary to maintain those cellular states. The physiologic regulation of full length MST1/MST2 is controlled by the availability of its noncatalytic SARAH domain partners. Interaction with Sav1/WW45 recruits MST1/MST2 into a tumor suppressor pathway, wherein it phosphorylates and activates the Sav1-bound protein kinases Lats1/Lats2, potent inhibitors of the Yap1 and TAZ oncogenic transcriptional regulators. A constitutive interaction with the Rap1-GTP binding protein RASSF5B (Nore1B/RAPL) in T cells recruits MST1 (especially) and MST2 as an effector of Rap1's control of T cell adhesion and migration, a program crucial to immune surveillance and response; loss of function mutation in human MST1 results in profound immunodeficiency. MST1 and MST2 are also regulated by other protein kinases, positively by TAO1 and negatively by Par1, SIK2/3, Akt, and cRaf1. The growing list of candidate MST1/MST2 substrates suggests that the full range of MST1/MST2's physiologic programs and contributions to pathophysiology remains to be elucidated.
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Affiliation(s)
- Jacob A. Galan
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Diabetes Unit and Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Joseph Avruch
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Diabetes Unit and Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States
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Kang W, Cheng ASL, Yu J, To KF. Emerging role of Hippo pathway in gastric and other gastrointestinal cancers. World J Gastroenterol 2016; 22:1279-1288. [PMID: 26811664 PMCID: PMC4716037 DOI: 10.3748/wjg.v22.i3.1279] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/15/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
More evidence has underscored the importance of Hippo signaling pathway in gastrointestinal tissue homeostasis, whereas its deregulation induces tumorigenesis. Yes-associated protein 1 (YAP1) and its close paralog TAZ, transcriptional co-activator with a PDZ-binding motif, function as key effectors negatively controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In various cancers, Hippo pathway cross-talks with pro- or anti-tumorigenic pathways such as GPCR, Wnt/β-catenin, Notch and TGF-β signaling and is deregulated by multiple factors including cell density/junction and microRNAs. As YAP1 expression is significantly associated with poor prognosis of gastric and other gastrointestinal cancers, detailed delineation of Hippo regulation in tumorigenesis provides novel insight for therapeutic intervention. In current review, we summarized the recent research progresses on the deregulation of Hippo pathway in the gastrointestinal tract including stomach and discuss the molecular consequences leading to tumorigenesis.
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RUNX3 is a novel negative regulator of oncogenic TEAD-YAP complex in gastric cancer. Oncogene 2015; 35:2664-74. [PMID: 26364597 DOI: 10.1038/onc.2015.338] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 07/11/2015] [Accepted: 07/31/2015] [Indexed: 02/06/2023]
Abstract
Runt-related transcription factor 3 (RUNX3) is a well-documented tumour suppressor that is frequently inactivated in gastric cancer. Here, we define a novel mechanism by which RUNX3 exerts its tumour suppressor activity involving the TEAD-YAP complex, a potent positive regulator of proliferative genes. We report that the TEAD-YAP complex is not only frequently hyperactivated in liver and breast cancer, but also confers a strong oncogenic activity in gastric epithelial cells. The increased expression of TEAD-YAP in tumour tissues significantly correlates with poorer overall survival of gastric cancer patients. Strikingly, RUNX3 physically interacts with the N-terminal region of TEAD through its Runt domain. This interaction markedly reduces the DNA-binding ability of TEAD that attenuates the downstream signalling of TEAD-YAP complex. Mutation of RUNX3 at Arginine 122 to Cysteine, which was previously identified in gastric cancer, impairs the interaction between RUNX3 and TEAD. Our data reveal that RUNX3 acts as a tumour suppressor by negatively regulating the TEAD-YAP oncogenic complex in gastric carcinogenesis.
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Abstract
RUNX proteins belong to a family of metazoan transcription factors that serve as master regulators of development. They are frequently deregulated in human cancers, indicating a prominent and, at times, paradoxical role in cancer pathogenesis. The contextual cues that direct RUNX function represent a fast-growing field in cancer research and could provide insights that are applicable to early cancer detection and treatment. This Review describes how RUNX proteins communicate with key signalling pathways during the multistep progression to malignancy; in particular, we highlight the emerging partnership of RUNX with p53 in cancer suppression.
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Affiliation(s)
- Yoshiaki Ito
- 1] Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, 14 Medical Drive #12-01, 117599, Singapore. [2]
| | - Suk-Chul Bae
- 1] Department of Biochemistry, School of Medicine, and Institute for Tumour Research, Chungbuk National University, Cheongju, 361763, South Korea. [2]
| | - Linda Shyue Huey Chuang
- 1] Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, 14 Medical Drive #12-01, 117599, Singapore. [2]
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Du X, Yu A, Tao W. The non-canonical Hippo/Mst pathway in lymphocyte development and functions. Acta Biochim Biophys Sin (Shanghai) 2015; 47:60-4. [PMID: 25487919 DOI: 10.1093/abbs/gmu112] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The canonical Hippo/Mst pathway, originally discovered in Drosophila, is famous for its function in promoting apoptosis, inhibiting cell proliferation and tumorigenesis, and regulating tissue regeneration. However, emerging evidence shows that multiple non-canonical Hippo signaling pathways are also implicated in the regulation of various other biological processes. Recent studies have revealed that Mst1/2, the core kinases of Hippo/Mst pathway are required for T cell development, function, survival, trafficking, and homing, and also involved in regulation of autoimmunity. In this review, we discuss the roles of non-canonical Hippo/Mst signaling pathways in lymphocyte development and functions.
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Affiliation(s)
- Xingrong Du
- State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Scholl of Life Sciences, Fudan University, Shanghai 200433, China
| | - Alan Yu
- University of Toronto, Toronto, Ontario M5S2J7, Canada
| | - Wufan Tao
- State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Scholl of Life Sciences, Fudan University, Shanghai 200433, China
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Li XJ, Park ES, Park MH, Kim SM. 3,3'-Diindolylmethane suppresses the growth of gastric cancer cells via activation of the Hippo signaling pathway. Oncol Rep 2013; 30:2419-26. [PMID: 24008339 DOI: 10.3892/or.2013.2717] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 08/23/2013] [Indexed: 12/11/2022] Open
Abstract
Recent studies have revealed that 3,3-diindolylmethane (DIM) has antitumor effects in both in vivo and in vitro tumor models. However, the biological function of DIM in human gastric cancer cells is unknown. Genetic and biological studies have confirmed the importance of the novel Hippo tumor-suppressor pathway in regulating cell proliferation, apoptosis, organ size and tumorigenesis in mammals. Thus, the purpose of this study was to investigate the cytotoxic effects of DIM in human gastric cancer cells and to elucidate whether DIM induces cell death by activating the Hippo signaling pathway. Two human gastric cancer cell lines (SNU-1 and SNU-484) were used to investigate the DIM response. DIM significantly inhibited the proliferation of human gastric cancer cells in a dose-dependent manner. The percentage of G1 phase cells increased 24 h following DIM treatment. DIM reduced CDK2, CDK4, CDK6 and cyclin D1 protein levels, while increasing p53 protein levels. DIM induced the levels of cleaved poly(ADP-ribose) polymerase, cleaved-caspase-9, and diminished pro-caspase-3 protein production. In addition, DIM increased pLATS1, Mob1, pMob1, pYAP and Ras association domain family 1 (RASSF1) protein levels and reduced Yap protein production levels. DIM stimulated the binding of RASSF1 with the Mst1/2-LATS1-Mob1 complex, promoting an active Hippo signaling pathway and favoring YAP phosphorylation (pYAP) that inactivates cell proliferation. Furthermore, DIM inhibited the growth of human gastric tumors in a xenograft mouse model. These results indicate that DIM suppresses the growth of gastric cancer cells by activating the Hippo signaling pathway.
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Affiliation(s)
- Xiu Juan Li
- Department of Physiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea
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Bernascone I, Martin-Belmonte F. Crossroads of Wnt and Hippo in epithelial tissues. Trends Cell Biol 2013; 23:380-9. [PMID: 23607968 DOI: 10.1016/j.tcb.2013.03.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 03/13/2013] [Accepted: 03/15/2013] [Indexed: 12/22/2022]
Abstract
Epithelial tissues undergo constant growth and differentiation during embryonic development and to replace damaged tissue in adult organs. These processes are governed by different signaling pathways that ultimately control the expression of genes associated with cell proliferation, patterning, and death. One essential pathway is Wnt, which controls tubulogenesis in several epithelial organs. Recently, Wnt has been closely linked to other signaling pathways, such as Hippo, that orchestrate proliferation and apoptosis to control organ size. There is evidence that epithelial cell junctions may sequester the transcription factors that act downstream of these signaling pathways, which would represent an important aspect of their functional regulation and their influence on cell behavior. Here, we review the transcriptional control exerted by the Wnt and Hippo signaling pathways during epithelial growth, patterning, and differentiation and recent advances in understanding of the regulation and crosstalk of these pathways in epithelial tissues.
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Affiliation(s)
- Ilenia Bernascone
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), C/Nicolás Cabrera 1, Madrid 28049, Spain
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Chuang LSH, Ito K, Ito Y. RUNX family: Regulation and diversification of roles through interacting proteins. Int J Cancer 2012. [PMID: 23180629 DOI: 10.1002/ijc.27964] [Citation(s) in RCA: 151] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Runt-related transcription factors (RUNX) belong to an ancient family of metazoan genes involved in developmental processes. Through multiple protein-interacting partners, RUNX proteins have been implicated in diverse signaling pathways and cellular processes. The frequent inactivation of RUNX genes in cancer indicates crucial roles for RUNX in tumor suppression. This review discusses the abilities of RUNX proteins, in particular RUNX3, to integrate oncogenic signals or environmental cues and to initiate appropriate tumor suppressive responses.
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