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Cell Rep. 2014 Jul 10;8(1):204-16. doi: 10.1016/j.celrep.2014.05.045. Epub 2014 Jun 19.

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

Author information

1
Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A(∗)STAR), Biopolis, Singapore 138672, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore.
2
Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A(∗)STAR), Biopolis, Singapore 138672, Singapore.
3
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore.
4
Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A(∗)STAR), Biopolis, Singapore 138672, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore 169857, Singapore. Electronic address: yuq@gis.a-star.edu.sg.

Abstract

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.

PMID:
24953652
DOI:
10.1016/j.celrep.2014.05.045
[Indexed for MEDLINE]
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