β
Menée in vitro et in vivo, cette étude met en évidence le rôle joué par le complexe transcriptionnel YAP1 dans la survie des cellules cancéreuses dépendant de la signalisation de la
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. º
β
-catenin-dependent cancers require YAP1 expression for survival º
β
-catenin, YAP1, and TBX5 form a complex that drives expression of BIRC5 and BCL2L1 º YES1 regulates the activity of the
β
-catenin-YAP1-TBX5 complex º The YES1 inhibitor dasatinib inhibits the proliferation of
β
-catenin-active cells Loss-of-function screens and
β
-catenin activity profiling in 85 cancer cell lines identified a transcriptional complex composed of YAP1, a known mediator of Hippo signaling, the transcription factor TBX5, and
β
-catenin. This complex is essential for the proliferation and tumorigenicity of
β
-catenin-active cell lines.