β-catenin–Driven Tumors Are Dependent on a YAP1 Transcriptional Complex

Mutations in the WNT pathway result in oncogenic β-catenin activity that promotes the initiation and progression of colon cancer. Stabilization of β-catenin triggers its interaction with transcription factor 4 (TCF4) to stimulate the expression of proproliferative genes; however, β-catenin also interacts with other transcriptional regulators, suggesting that it may contribute to tumorigenesis by other mechanisms. Rosenbluh and colleagues combined data from loss-of-function screens with a β-catenin/TCF4 reporter assay in 85 cancer cell lines and identified 50 genes that were required specifically for the survival of cells with active β-catenin signaling. In particular, downregulation of Yes-associated protein 1 (YAP1), a transcriptional coactivator that has been implicated as an oncogene, suppressed the proliferation and anchorage-independent growth of these cells and significantly reduced tumor growth. Moreover, expression of either β-catenin or YAP1 was sufficient for oncogenic transformation, suggesting that these proteins cooperate to enhance tumorigenesis. Consistent with this idea, β-catenin, YAP1, and the transcription factor T-box 5 (TBX5) formed a complex that induced the expression of antiapoptotic genes, including BCL2-like 1 (BCL2L1) and baculoviral IAP repeat containing 5 (BIRC5), independent of TCF4 and known YAP1 coactivators. This effect was dependent on phosphorylation of YAP1 by v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES1), which mediated the interaction of these transcription factors and localization of this complex to the BCL2L1 and BIRC5 promoters. Inhibition of YES1 kinase activity with dasatinib impaired normal zebrafish gut development and the growth of β-catenin–active cancer cell lines and reversed β-catenin–driven proliferation in primary murine colon organoids and a zebrafish model of intestinal hyperplasia. These results support a critical role for this β-catenin–YAP1 complex in colon cancer pathogenesis and suggest that targeted blockade of YES1 may provide therapeutic benefit to patients with β-catenin–activated cancers.

Rosenbluh J, Nijhawan D, Cox AG, Li X, Neal JT, Schafer EJ, et al. β-catenin–driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 2012;151:1457–73.