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PLoS One. 2015 Jun 1;10(6):e0126466. doi: 10.1371/journal.pone.0126466. eCollection 2015.

Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways.

Author information

1
Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
2
Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
3
Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
4
Department of Structural and Chemical Biology, Icahn School of Medicine, Mt Sinai Hospital, New York, New York, United States of America.
5
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
6
Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
7
Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada.

Abstract

Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator induced in many cancers. It is thought to drive tumorigenesis by repressing division, stemness, and/or developmental regulators. Cancers evade immune detection, and diverse immune regulators are perturbed in different tumors. It is unclear how such cell-specific effects are coordinated. Here, we show a profound and cancer-selective role for PRC2 in repressing multiple cytokine pathways. We find that PRC2 represses hundreds of IFNγ stimulated genes (ISGs), cytokines and cytokine receptors. This target repertoire is significantly broadened in cancer vs non-cancer cells, and is distinct in different cancer types. PRC2 is therefore a higher order regulator of the immune program in cancer cells. Inhibiting PRC2 with either RNAi or EZH2 inhibitors activates cytokine/cytokine receptor promoters marked with bivalent H3K27me3/H3K4me3 chromatin, and augments responsiveness to diverse immune signals. PRC2 inhibition rescues immune gene induction even in the absence of SWI/SNF, a tumor suppressor defective in ~20% of human cancers. This novel PRC2 function in tumor cells could profoundly impact the mechanism of action and efficacy of EZH2 inhibitors in cancer treatment.

PMID:
26030458
PMCID:
PMC4450877
DOI:
10.1371/journal.pone.0126466
[Indexed for MEDLINE]
Free PMC Article

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