EZH2-mediated inactivation of IFN-γ-JAK-STAT1 signaling is an effective therapeutic target in MYC-driven prostate cancer.

Although small-molecule targeting of EZH2 appears to be effective in lymphomas carrying EZH2 activating mutations, finding similar approaches to target EZH2-overexpressing epithelial tumors remains challenging. In MYC-driven, but not PI3K-driven prostate cancer, we show that interferon-γ receptor 1 (IFNGR1) is directly repressed by EZH2 in a MYC-dependent manner and is downregulated in a subset of metastatic prostate cancers. EZH2 knockdown restored the expression of IFNGR1 and, when combined with IFN-γ treatment, led to strong activation of IFN-JAK-STAT1 tumor-suppressor signaling and robust apoptosis. Pharmacologic depletion of EZH2 by the histone-methylation inhibitor DZNep mimicked the effects of EZH2 knockdown on IFNGR1 induction and delivered a remarkable synergistic antitumor effect with IFN-γ. In contrast, although they efficiently depleted histone Lysine 27 trimethylation, EZH2 catalytic inhibitors failed to mimic EZH2 depletion. Thus, EZH2-inactivated IFN signaling may represent a therapeutic target, and patients with advanced prostate cancer driven by MYC may benefit from the combination of EZH2 and IFN-γ-targeted therapy.

• Publication year

  2014

• Venue

  Cell Reports

• Publication date

  2014-07-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.celrep.2014.05.045PMID 24953652
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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