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

SUMMARY Wnt/b-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic b-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of b-catenin in transformation, we classified b-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that b-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 b-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 smallmolecule inhibitor of YES1 impeded the proliferation of b-catenin-dependent cancers in both cell lines and animal models. These observations define a b-catenin-YAP1-TBX5 complex essential to the transformation and survival of b-catenin-driven cancers.