Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth

Zanconato, Francesca; Forcato, Mattia; Battilana, Giusy; Azzolin, Luca; Quaranta, Erika; Bodega, Beatrice; Rosato, Antonio; Bicciato, Silvio; Cordenonsi, Michelangelo; Piccolo, Stefano

doi:10.1038/ncb3216

Cited by 965 publications

(1,222 citation statements)

References 58 publications

(96 reference statements)

Supporting

115

Mentioning

1,101

Contrasting

Unclassified

Order By: Relevance

“…4B). In addition, it has been reported that several genes are regulated by YAP, including connective tissue growth factor (CTGF) and Cyr6128, 29, 30, 31. We next examined the mRNA levels of the two genes by real‐time quantitative RT‐PCR.…”

Section: Resultsmentioning

confidence: 99%

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

Zhang

Yan

Chen

et al. 2017

J Cellular Molecular Medi

View full text Add to dashboard Cite

WWC family proteins negatively regulate HEK293 cell proliferation and organ growth by suppressing the transcriptional activity of Yes‐associated protein (YAP), a major effector of the Hippo pathway. The function of the scaffolding protein WWC1 (also called KIBRA) has been intensively studied in cells and animal models. However, the expression and clinicopathologic significance of WWC2 in cancer are poorly characterized. This study aimed to clarify the biological function and mechanism of action of WWC2 in hepatocellular carcinoma (HCC). Retrospective analysis revealed WWC2 was significantly down‐regulated in 95 clinical HCC tissues compared to the paired adjacent non‐cancerous tissues. Moreover, loss of WWC2 expression was significantly associated with advanced clinicopathological features, including venous infiltration, larger tumour size and advanced TNM stage. Positive WWC2 expression was associated with significantly better 5‐year overall survival, and WWC2 was an independent prognostic factor for overall survival in HCC. Moreover, we confirmed WWC2 inhibits HCC cell invasive ability in vitro. Elevated YAP expression was also observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated WWC2 expression correlated inversely with nuclear YAP protein expression in HCC. Mechanistically, we confirmed overexpression of WWC2 suppresses the invasive and metastatic potential of HCC cells by activating large tumour suppressor 1 and 2 kinases (LATS1/2), which in turn phosphorylates the transcriptional co‐activator YAP. Overall, this study indicates WWC2 functions as a tumour suppressor by negatively regulating the Hippo signalling pathway and may serve as a prognostic marker in HCC.

show abstract

Section: Resultsmentioning

confidence: 99%

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

Zhang

Yan

Chen

et al. 2017

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…It would be worthwhile to further delineate the Hippo signaling cascade and the cross-talk between the flow-sensitive pathways that modulate YAP/TAZ activities. YAP/TAZTEADs complex has been shown to induce expressions of its target genes controlling cell growth and cell cycle progression (9,27). It is likely that the OS-activated YAP/TAZ act through TEADs to promote EC proliferation.…”

Section: Discussionmentioning

confidence: 99%

Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

Wang

Yeh

Nguyen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

365

352

View full text Add to dashboard Cite

The focal nature of atherosclerotic lesions suggests an important role of local hemodynamic environment. Recent studies have demonstrated significant roles of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in mediating mechanotransduction and vascular homeostasis. The objective of this study is to investigate the functional role of YAP/TAZ in the flow regulation of atheroprone endothelial phenotypes and the consequential development of atherosclerotic lesions. We found that exposure of cultured endothelial cells (ECs) to the atheroprone disturbed flow resulted in YAP/TAZ activation and translocation into EC nucleus to up-regulate the target genes, including cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), and ankyrin repeat domain 1 (ANKRD1). In contrast, the atheroprotective laminar flow suppressed YAP/TAZ activities. En face analysis of mouse arteries demonstrated an increased nuclear localization of YAP/TAZ and elevated levels of the target genes in the endothelium in atheroprone areas compared with athero-protective areas. YAP/TAZ knockdown significantly attenuated the disturbed flow induction of EC proliferative and proinflammatory phenotypes, whereas overexpression of constitutively active YAP was sufficient to promote EC proliferation and inflammation. In addition, treatment with statin, an antiatherosclerotic drug, inhibited YAP/TAZ activities to diminish the disturbed flow-induced proliferation and inflammation. In vivo blockade of YAP/TAZ translation by morpholino oligos significantly reduced endothelial inflammation and the size of atherosclerotic lesions. Our results demonstrate a critical role of the activation of YAP/TAZ by disturbed flow in promoting atheroprone phenotypes and atherosclerotic lesion development. Therefore, inhibition of YAP/TAZ activation is a promising athero-protective therapeutic strategy.atherogenesis | disturbed flow | endothelial cells | mechanotransduction

show abstract

“…In this study, we observed that FGFR1, -2, and -4 are direct transcriptional targets of YAP. Although the cognate YAP transcription factors are TEADs (34,35), in CCA cells YAP partners with TBX5 to promote up-regulation of FGFR1, -2, and -4. Prior studies have demonstrated an essential role for ␤-catenin-YAP-TBX5 in tumors with activated WNT signaling (6).…”

Section: Discussionmentioning

confidence: 99%

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Rizvi

Yamada

Hirsova

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cholangiocarcinomas are highly lethal hepatobiliary cancers with features of cholangiocyte differentiation (1). Although the incidence of CCA 4 is increasing in Western countries (2), therapeutic options for advanced disease not amenable to surgical extirpation remain limited, and overall survival rates are less than 10% (3). Treatment options for advanced CCA are limited, in part, because of the genetic heterogeneity of this malignancy and an incomplete understanding of CCA signaling pathways and biology. There is a critical need to elucidate the molecular mechanisms underlying CCA pathogenesis so that targeted, individualized therapies coupled with biomarkers may be developed (4). Hippo, a highly conserved growth control pathway, is deregulated in several human malignancies (5-7) including human CCA (8, 9). Recently, we reported that direct transfection of the biliary tree with a constitutively active mediator of the Hippo pathway, YAPS127A, along with mouse myr-Akt as a permissive factor, induces CCA in mice (10). This observation directly implicates oncogenic Hippo pathway signaling in CCA biology. The core machinery of the Hippo pathway consists of a kinase relay module and a transcriptional module (11). When the kinase module is "on" it inactivates the transcriptional module, and when it is "off" the transcriptional module becomes active (11). The core components of the kinase module consist of the serine/threonine kinases MST1 and MST2, large tumor suppressor 1 (LATS1), and LATS2 (6). The downstream kinases LATS1 and LATS2 directly phosphorylate the mediators of the transcriptional module, the co-transcriptional activators YAP, and its paralog TAZ, resulting in their inactivation (12). Indeed, the phosphorylation of YAP and TAZ results in their nuclear export, cytoplasmic retention, and/or degradation by the proteasome (6). Although YAP and TAZ have functional redundancy, they also have distinct functions, and accordingly YAP, but not TAZ, has been more strongly implicated in cancer biology to date. The Hippo pathway has been implicated in CCA biology based mainly on nuclear localization of YAP by immunohistochemistry (8), a finding suggesting disruption of the kinase module by yet undefined mechanisms. The Hippo pathway is unique in that it does not have an extracellular ligand or a dedicated plasma membrane receptor and therefore must be activated by cross-talk mechanisms.Fibroblast growth factor receptors (FGFR) are also deregulated in a myriad of malignancies (13). Recently, we and others have described FGFR2 gene fusions in solid organ malignancies including CCA (10 -15% prevalence in CCA) (4, 14 -17). * This work was supported by National Institutes of Health Grants DK59427(to G. J. G.), T32DK007198 (to S. R.), DK84567 (Optical Microscopy Core for the Mayo Center for Cell Signaling in Gastroenterology), and ES020715 (to E. T.) and by the Mayo Foundation. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the auth...

show abstract

Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth

Cited by 965 publications

References 58 publications

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Contact Info

Product

Resources

About