KRAS and YAP1 converge to regulate EMT and tumor survival
By Diane D. Shao, W. Xue, E. Krall, A. Bhutkar, F. Piccioni, Xiaoxing Wang, Anna C. Schinzel, S. Sood, Joseph Rosenbluh, Jong Wook Kim and 5 more. Cell, 2014
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Summary 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 co-activator 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.
Subfields: Cell Biology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/c5edfeab5d34ba78bf290050fa1e97349c1b40ea
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Citations in the corpus
- Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, positive): “Amplification of the YAP gene has been associated with cancer relapse in KRAS-driven colon and pancreatic cancers (Kapoor et al., 2014; Shao et al., 2014).”
- Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. (2018, background): “Numerous reports have observed heterogeneous dependence for sustained KRAS expression (<50% addicted) across KRASmutant cancer cell lines (Hayes et al., 2016; Kapoor et al., 2014; Lamba et al., 2014; Patricelli et al., 2016; Shao et al., 2014; Singh et al., 2009; Sunaga et al., 2011; Vartanian et al”
- Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “YAP was shown to cooperate with KRAS for progression of pancreatic cancer and TAZ is a promoter of proliferation, EMT and stemness in breast and oral cancer (Zhang et al , 2009 ; Shao et al , 2014 ; Li et al , 2015 ; Debaugnies et al , 2018 ).”
- KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer (2018, background): “One mechanism by which PDAC loses its addiction to KRAS is through activation and expression of the Hippo pathway component YAP1 (Kapoor et al. 2014; Shao et al. 2014).”
- Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis (2015, methodology): “RNAi and overexpression of open reading frames (ORFs) have been utilized for screening cancer genes in several models of oncogenesis in mice (Schramek et al., 2014; Shao et al., 2014; Zender et al., 2008).”
- The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “Two recent papers studied the mechanism of tumor recurrence after K-Ras inhibition and intriguingly linked the rescue of cell survival of otherwise K-Ras-addicted tumor cells to YAP1 activation (100, 184).”
- YAP/TAZ at the roots of cancer (2016, background): “Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F, Wang X, Schinzel AC, Sood S, Rosenbluh J, Kim JW, et al. KRAS and YAP1 converge to regulate EMT and tumor survival.”
- The Hippo Signaling Pathway in Development and Disease (2019, background): “, 2014) and lung cancer (Shao et al., 2014) also lead to YAP activation.”
- Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (2014, positive): “The ability of Yap to drive Krasindependent cell growth aligns with the ability of enforced Yap1 to complement loss of Kras function in human pancreatic cancer cell lines (Shao et al., 2014).”