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

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

SUBMITTER: Rosenbluh J 

PROVIDER: S-EPMC3530160 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature