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