title: EZH2-mediated inactivation of IFN-γ-JAK-STAT1 signaling is an effective therapeutic target in MYC-driven prostate cancer.
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.
authors: 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.
authors: Zhen Ning
authors: ZN
authors: Wee
authors: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A(∗)STAR), Biopolis, Singapore 138672, Singapore.
authors: Zhimei
authors: Z
authors: Li
authors: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A(∗)STAR), Biopolis, Singapore 138672, Singapore.
authors: Puay Leng
authors: PL
authors: Lee
authors: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A(∗)STAR), Biopolis, Singapore 138672, Singapore.
authors: Shuet Theng
authors: ST
authors: Lee
authors: 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.
authors: Yoon Pin
authors: YP
authors: Lim
authors: 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.
authors: Qiang
authors: Q
authors: Yu
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000096743:Interferon gamma Receptor
chemical_list: D000241:Adenosine; D000071221:Enhancer of Zeste Homolog 2 Protein; D007371:Interferon-gamma; D053612:Janus Kinases; D063151:Polycomb Repressive Complex 2; D016271:Proto-Oncogene Proteins c-myc; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C048460:3-deazaneplanocin; C498409:EZH2 protein, human