In intestinal tissues of mice, PRC2 maintains small intestinal stem cells by promoting proliferation and preventing differentiation in the intestinal stem cell compartment. PRC2 controls gene expression in multiple signaling pathways that regulate intestinal homeostasis. Sequencing data are available in the genomics data repository GEO under reference series GSE81578; RNA sequencing data are available under subseries GSE81576; and ChIP sequencing data are available under subseries GSE81577.

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.

Polycomb Group (PcG) proteins form Polycomb Repressive Complexes (PRCs) that function as epigenetic repressors of gene expression. The large variety of PcG proteins, in addition to the high number of paralogs, allows for the formation of diverse PRCs with different properties, providing fine-tuned control over cell specification. Initially identified as being oncogenes, a small number of PcG genes are involved in tumor development in part through the repression of the CDKN2A locus. Therefore, enhanced PcG-mediated repression has long been assumed to be cancer promoting. However, recent data have revealed that for some cancers, PcG proteins act as tumor suppressors, indicating that this traditional view is oversimplified. In this review, we present an overview of the roles of PcG genes in oncogenesis and how the nature of their role is context dependent.