β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis

Wnt/beta-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic beta-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of beta-catenin in transformation, we classified beta-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that beta-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 beta-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 beta-catenin-dependent cancers in both cell lines and animal models. These observations define a beta-catenin-YAP1-TBX5 complex essential to the transformation and survival of beta-catenin-driven cancers.