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

Serresi, M; Gargiulo, G; Proost, N; Siteur, B; Cesaroni, M; Koppens, M; Xie, H; Sutherland, KD; Hulsman, D; Citterio, E; Orkin, S; Berns, A; van Lohuizen, M

Author(s): Serresi, M; Gargiulo, G; Proost, N; Siteur, B; Cesaroni, M; Koppens, M; Xie, H; Sutherland, KD; Hulsman, D; Citterio, E; Orkin, S; Berns, A; van Lohuizen, M;
Details: Publication Year 2016-01-11,Volume 29,Issue #1,Page 17-31
Journal Title: Cancer Cell
Publication Type: Journal Article
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.
Publisher: Cell Press
Research Division(s): Stem Cells And Cancer
PubMed ID: 26766588
Publisher's Version: https://doi.org/10.1016/j.ccell.2015.12.006
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-03-14 03:05:31

Last Modified: 2016-03-14 03:51:20