EZH2-Mediated Inactivation of IFN-γ-JAK-STAT1 Signaling Is an Effective Therapeutic Target in MYC-Driven Prostate Cancer

• IFNGR1 is a target of EZH2 in Myc-driven advanced prostate cancer
• Depletion of EZH2 restores defective IFN-IFNGR1-STAT1 signaling
• Pharmacologic depletion of EZH2 synergizes with IFN-γ in vitro and in vivo
• Catalytic inhibitors of EZH2 fail to mimic EZH2 depletion

SummaryAlthough 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.

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