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

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 enha...

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Vydáno v:Cancer cell Ročník 29; číslo 1; s. 17
Hlavní autoři: Serresi, Michela, Gargiulo, Gaetano, Proost, Natalie, Siteur, Bjorn, Cesaroni, Matteo, Koppens, Martijn, Xie, Huafeng, Sutherland, Kate D, Hulsman, Danielle, Citterio, Elisabetta, Orkin, Stuart, Berns, Anton, van Lohuizen, Maarten
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 11.01.2016
Témata:
Acetylation
Animals
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - metabolism
Cell Proliferation - genetics
Cell Proliferation - physiology
Disease Models, Animal
Enhancer of Zeste Homolog 2 Protein
Epithelial-Mesenchymal Transition - genetics
Histones - metabolism
Humans
Inflammation - genetics
Inflammation - metabolism
Mice, Transgenic
Polycomb Repressive Complex 2 - genetics
Polycomb Repressive Complex 2 - metabolism
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
ISSN:1878-3686, 1878-3686
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2015.12.006