β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis

Cell. 2012 Dec 21;151(7):1457-73. doi: 10.1016/j.cell.2012.11.026.

Joseph Rosenbluh ¹, Deepak Nijhawan, Andrew G Cox, Xingnan Li, James T Neal, Eric J Schafer, Travis I Zack, Xiaoxing Wang, Aviad Tsherniak, Anna C Schinzel, Diane D Shao, Steven E Schumacher, Barbara A Weir, Francisca Vazquez, Glenn S Cowley, David E Root, Jill P Mesirov, Rameen Beroukhim, Calvin J Kuo, Wolfram Goessling, William C Hahn

Affiliations

Affiliation

1 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

PMID: 23245941 DOI: 10.1016/j.cell.2012.11.026

Abstract

Wnt/β-catenin signaling plays a key role in the pathogenesis of colon and Other cancers; emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for Cancer initiation and progression. To decipher the role of β-catenin in transformation, we classified β-catenin activity in 85 Cancer cell lines in which we performed genome-scale loss-of-function screens and found that β-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with β-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of β-catenin-dependent cancers in both cell lines and animal models. These observations define a β-catenin-YAP1-TBX5 complex essential to the transformation and survival of β-catenin-driven cancers.

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