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Cell. 2014 Jul 3;158(1):171-84. doi: 10.1016/j.cell.2014.06.004. Epub 2014 Jun 19.

KRAS and YAP1 converge to regulate EMT and tumor survival.

Author information

  • 1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 2Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA.
  • 3Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 4Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
  • 5Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: tjacks@mit.edu.
  • 6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: william_hahn@dfci.harvard.edu.

Abstract

Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling.

PMID:
24954536
PMCID:
PMC4110062
DOI:
10.1016/j.cell.2014.06.004
[PubMed - indexed for MEDLINE]
Free PMC Article
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