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Polycomb repressive complex 2 is a barrier to KRAS-driven inflammation and epithelial-mesenchymal transition in non-small-cell lung cancer

Item Type:Article
Title:Polycomb repressive complex 2 is a barrier to KRAS-driven inflammation and epithelial-mesenchymal transition in non-small-cell lung cancer
Creators Name:Serresi, M. and Gargiulo, G. and Proost, N. and Siteur, B. and Cesaroni, M. and Koppens, M. and Xie, H. and Sutherland, K.D. and Hulsman, D. and Citterio, E. and Orkin, S. and Berns, A. and van Lohuizen, M.
Abstract:Polycomb repressive complexes (PRC) are frequently implicated in human cancer, acting either as oncogenes or tumor suppressors. Here, we show that PRC2 is a critical regulator of KRAS-driven non-small cell lung cancer progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances KRAS-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell-autonomous epithelial-to-mesenchymal transition program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application.
Keywords:Acetylation, Animal Disease Models, Cell Proliferation, Epithelial-Mesenchymal Transition, Histones, Inflammation, Non-Small-Cell Lung Carcinoma, Polycomb Repressive Complex 2, Proto-Oncogene Proteins p21(ras), Transgenic Mice, Animals, Mice
Source:Cancer Cell
ISSN:1535-6108
Publisher:Cell Press / Elsevier (U.S.A.)
Volume:29
Number:1
Page Range:17-31
Date:11 January 2016
Additional Information:Erratum in: Cancer Cell 29(2):241.
Official Publication:https://doi.org/10.1016/j.ccell.2015.12.006
PubMed:View item in PubMed

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