Journal
CELL
Volume 151, Issue 7, Pages 1457-1473Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.11.026
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Funding
- NIH/NCI [R01 CA140545, RC2 CA148268, U54 CA143798, U01 DK085527, U01 CA151920, R01 DK085720, U54 CA112962, R01 DK090311]
- Pew Charitable Trust
- Fidelity Foundation
- Stanford University
- DoD [W81XWH-10-1-0062]
- Conquer Cancer Foundation
- Sass Foundation
- SPORE career development award [P50 CA127003]
- NIH [F32 GM090437]
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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.
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