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

Cell. 2012 Dec 21;151(7):1457-73. doi: 10.1016/j.cell.2012.11.026. Epub 2012 Dec 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic*
  • Colon / embryology
  • Colon / metabolism
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Mice
  • Mice, Nude
  • Phosphoproteins / metabolism*
  • Proto-Oncogene Proteins c-yes / antagonists & inhibitors
  • Proto-Oncogene Proteins c-yes / metabolism
  • Survivin
  • T-Box Domain Proteins / metabolism*
  • Transcription Factors
  • Transcription, Genetic
  • Zebrafish / embryology
  • bcl-X Protein / genetics
  • beta Catenin / metabolism*
  • src-Family Kinases / antagonists & inhibitors

Substances

  • Adaptor Proteins, Signal Transducing
  • BCL2L1 protein, human
  • BIRC5 protein, human
  • CTNNB1 protein, human
  • Inhibitor of Apoptosis Proteins
  • Phosphoproteins
  • Survivin
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • bcl-X Protein
  • beta Catenin
  • Proto-Oncogene Proteins c-yes
  • YES1 protein, human
  • src-Family Kinases