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Cell DOI:10.1016/j.cell.2014.06.004

KRAS and YAP1 converge to regulate EMT and tumor survival.

Publication TypeJournal Article
Year of Publication2014
AuthorsShao, DD, Xue, W, Krall, EB, Bhutkar, A, Piccioni, F, Wang, X, Schinzel, AC, Sood, S, Rosenbluh, J, Kim, JW, Zwang, Y, Roberts, TM, Root, DE, Jacks, T, Hahn, WC
Date Published2014 Jul 03
KeywordsAdaptor Proteins, Signal Transducing, Animals, Cell Survival, Colonic Neoplasms, Drug Delivery Systems, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, HCT116 Cells, Humans, Lung Neoplasms, Mice, Phosphoproteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Signal Transduction, Transcriptional Activation

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.


Alternate JournalCell
PubMed ID24954536
PubMed Central IDPMC4110062
Grant ListP30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
K99 CA169512 / CA / NCI NIH HHS / United States
R00 CA169512 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 CA140545 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
P01 CA050661 / CA / NCI NIH HHS / United States