Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer.
Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer.
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DOI：
10.1158/1940-6207.capr-20-0186
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Ellis L
中科院分区：
文献类型：
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作者：
Burkhart DL;Morel KL;Wadosky KM;Labbé DP;Galbo PM;Dalimov Z;Xu B;Loda M;Ellis L
通过雄激素受体或雄激素合成抑制来预防前列腺癌（PCa）的实验已被证明是无效的。最近，已经证明组蛋白甲基转移酶EZH 2在小鼠和人高级前列腺上皮内瘤变（HG-PIN）中失调。使用PCa的临床前小鼠和人类模型，我们证明了EZH 2表达和催化活性的遗传和化学破坏逆转了HG-PIN表型。此外，EZH 2功能的抑制与细胞增殖的丧失和Tp 53依赖性衰老的诱导相关。总之，这些数据为EZH 2作为预防前列腺癌的可行治疗靶点提供了挑衅性证据。
Chemoprevention trials for prostate cancer (PCa) by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is de-regulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using pre-clinical mouse and human models of PCa, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype. Further, inhibition of EZH2 function was associated with loss of cellular proliferation and induction of Tp53 dependent senescence. Together, these data provide provocative evidence for EZH2 as an actionable therapeutic target towards prevention of prostate cancer.