title: Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways.
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.
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abou El Hassan
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Huang
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Manoja B K
authors.initials: MB
authors.lastname: Eswara
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Lan
authors.initials: L
authors.lastname: Song
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Liu
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sean
authors.initials: S
authors.lastname: McCurdy
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine, Mt Sinai Hospital, New York, New York, United States of America.
authors.forename: Anqi
authors.initials: A
authors.lastname: Ma
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Joan
authors.initials: J
authors.lastname: Wither
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine, Mt Sinai Hospital, New York, New York, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: 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.
authors.forename: Rod
authors.initials: R
authors.lastname: Bremner
mesh_terms: D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C430461:SUZ12 protein, human; D054852:Small Molecule Libraries; D014157:Transcription Factors; D007371:Interferon-gamma; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C084108:SMARCA4 protein, human; D004265:DNA Helicases