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.

Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™

“…Its anticancer activity has been demonstrated in in vitro and in vivo in broad-spectrum cancer types, including lung, kidney, leukemia and prostate (Fillmore et al, 2015;Fiskus et al, 2009;Kikuchi et al, 2012;Liu et al, 2014;Wee et al, 2014). Although more specific EZH2 inhibitors (e.g.…”

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

“…Data obtained in vitro in breast cancer showed that EZH2 specifically induces cell death in cancer cells but not in normal cells [83] . Moreover, in vivo studies showed that, treatments with some EZH2 inhibitors alone or in combination with other chemotherapeutic agents are well tolerated by mice resulting in minimal toxicity or modest weight loss of 10% [105,117,118] . Nevertheless, the studies described above demonstrated that EZH2 activity can behave differently in distinguishing neoplasms, and a singular inhibitor can be effective in certain kind of cancer but not in others.…”

“…Conversely, EZH2 catalytic inhibitors, although they efficiently reduced H3K27me3, failed to mimic EZH2 depletion. Therefore, patients with advanced prostate cancer driven by Myc could have benefits from a therapeutic depletion of EZH2, indicating that the ability of EZH2 to increase the sensitivity of cancer cells to interferon-γ is independent by its catalytic activity [118] . An important point for consideration, in order to understand if a drug is suitable for therapy, concerns taking into account its penetration into the organs.…”

“…Activity of EZH2 in Myc-driven tumors is strictly correlated to Myc amplification. Myc knockdown reduces levels of EZH2 and H3K27me3 at IFNGR1 promoter only in Mycamplified prostate cell lines; while in Myc-independent tumor growth, IFNGR1 inhibition seems to be related on DNA hypermethylation [118] . This evidence suggested that combination of EZH2 inhibition with interferon-γ could be a specific strategy for Myc-driven prostate tumors and can help to improve the outcome of patients.…”

3‐Deazaneplanocin A and Neplanocin A Analogues and Their Effects on Apoptotic Cell Death

“…Intriguingly, a recent study showed that although inhibitors of EZH2, such as GSK126, have robust activity in the depletion of H3K27me3 in epithelial tumors cells, they have little effect on cancer cell growth. [9] Moreover, a peptide that induces the depletion of EZH2 protein complex is sufficient to inhibit cell growth. [10] This raises a possibility that targeting the EZH2 complex, rather than inhibiting H3K27me3, is required for blocking the EZH2-mediated oncogenic effect.…”