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Cancer Cell. 2016 Jan 11;29(1):17-31. doi: 10.1016/j.ccell.2015.12.006.

Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer.

Author information

1
Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
2
Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. Electronic address: g.gargiulo@nki.nl.
3
Mouse Clinic Intervention Unit, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
4
The Fels Institute, Temple University School of Medicine, Philadelphia, PA 19140, USA.
5
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
6
Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Cancer Genomics Centre (CGC.nl), Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: m.v.lohuizen@nki.nl.

Erratum in

  • Cancer Cell. 2016 Feb 8;29(2):241.

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.

PMID:
26766588
DOI:
10.1016/j.ccell.2015.12.006
[Indexed for MEDLINE]
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