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

Joseph Rosenbluh, 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 GoesslingWilliam C. Hahn

Research output: Contribution to journalArticle

405 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1457-1473
Number of pages17
JournalCell
Volume151
Issue number7
DOIs
StatePublished - Dec 21 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Rosenbluh, J., Nijhawan, D., Cox, A. G., Li, X., Neal, J. T., Schafer, E. J., Zack, T. I., Wang, X., Tsherniak, A., Schinzel, A. C., Shao, D. D., Schumacher, S. E., Weir, B. A., Vazquez, F., Cowley, G. S., Root, D. E., Mesirov, J. P., Beroukhim, R., Kuo, C. J., ... Hahn, W. C. (2012). β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell, 151(7), 1457-1473. https://doi.org/10.1016/j.cell.2012.11.026