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.

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

“…3G). These results are consistent with previous observations in cancer cell lines that depletion of SUZ12, a subunit of the EZH2/1-PRC2 complex, resulted in the expression of a class of ISGs whose promoters exhibited bivalent (H3K27me3 and H3K4me3) histone methylation markers (54). The results are also complemented by analyses of data sets (GEO data set GSE81267) published by Qi et al (28) where treatment of Karpas422 cancer cells with a novel inhibitor targeting the PRC2 subunit EED (EED226) induced antipathogen gene cascades that parallel the inflammatory and stress pathways shown here ( Fig.…”

“…Thus, these inhibitors amplify cellular antiviral responses and contribute to the induction of immune cell responses in a context-dependent manner. The results are analogous to the synergistic/enhanced induction of ISGs in cells treated with both EZH2/1 inhibitors and IFN-␥, lipopolysaccharide, IL-1␤, or tumor necrosis factor alpha relative to treatment with each compound alone (54).…”

PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma

“…We identified genes induced upon type I and II interferon treatment in GBM cells and found that 40% of the EZH2-activated genes were induced by interferon treatment. Consistent with previously published data, a significant fraction (~40%) of the EZH2repressed genes also showed induction on interferon treatment (20). This suggests that EZH2 represses ISGs directly and also activates them indirectly by repressing miRNAs that target them.…”

“…Polycomb proteins and miRNAs have independently been implicated in the regulation of interferon genes (16,20,21). miRNAs have also been shown to activate expression of interferon pathway genes via repression of polycomb proteins (21).…”

Systematic prediction of target genes and pathways in cervical cancer from microRNA expression data

“…Cytokines can be grouped by structure into different families, as can and their receptors. It had been reported that the cytokine-cytokine receptor interaction gene set may induce cancer (41) and was upregulated in cancer cachexia (42); these changes should result in the development of markers for early diagnosis and a better understanding of the conditions of a tumor. Mak et al (43) revealed that the marked upregulation of genes involved in cytokine-cytokine receptor interactions were consistently detected in tumor cell lines.…”