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Inhibition of EZH2 enhances the antitumor efficacy of metformin in prostate cancer
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2020-10-06 , DOI: 10.1158/1535-7163.mct-19-0874
Yifan Kong 1, 2 , Yanquan Zhang 1 , Fengyi Mao 1, 2 , Zhuangzhuang Zhang 1 , Zhiguo Li 1 , Ruixin Wang 1 , Jinghui Liu 1 , Xiaoqi Liu 1, 3
Affiliation  

Upregulation of EZH2 is associated with advanced stage and poor prognosis of prostate cancer; therefore, it is likely to be a promising therapeutic target. Metformin, a drug that has been used to treat type 2 diabetes, was found to have antineoplastic activity in different cancers. Herein, we report that the combination of metformin and the EZH2 inhibitor GSK126 exerts synergistic inhibition on prostate cancer cell growth, both in vitro and in vivo. Mechanistically, we identify that metformin can reduce EZH2 expression through upregulating miR-26a-5p, which is antagonized by androgen receptor (AR). Furthermore, we show that AR binds to the promoter of miR-26a-5p and suppresses its transcription. Although metformin can remove AR from the miR-26a-5p promoter, the interaction between AR and EZH2, which usually exists in androgen-refractory prostate cancer cells, strongly impedes the removal. However, GSK126 can inhibit the methyltransferase-dependent interaction between AR and EZH2, thus restoring metformin's efficacy in androgen-refractory prostate cancer cells. Collectively, our finding suggests that the combination of metformin and GSK126 would be an effective approach for future prostate cancer therapy, and particularly effective for AR-positive castration-resistant prostate cancer.

中文翻译:

抑制 EZH2 增强二甲双胍在前列腺癌中的抗肿瘤功效

EZH2的上调与前列腺癌的晚期和不良预后有关;因此,它很可能是一个有希望的治疗靶点。二甲双胍是一种用于治疗 2 型糖尿病的药物,被发现在不同的癌症中具有抗肿瘤活性。在此,我们报告二甲双胍和 EZH2 抑制剂 GSK126 的组合在体外和体内对前列腺癌细胞生长发挥协同抑制作用。从机制上讲,我们发现二甲双胍可以通过上调 miR-26a-5p 来降低 EZH2 表达,miR-26a-5p 被雄激素受体 (AR) 拮抗。此外,我们显示 AR 与 miR-26a-5p 的启动子结合并抑制其转录。虽然二甲双胍可以从 miR-26a-5p 启动子中去除 AR,但 AR 与 EZH2 之间的相互作用,通常存在于雄激素难治性前列腺癌细胞中,强烈阻碍去除。然而,GSK126 可以抑制 AR 和 EZH2 之间依赖甲基转移酶的相互作用,从而恢复二甲双胍在雄激素难治性前列腺癌细胞中的疗效。总的来说,我们的发现表明二甲双胍和 GSK126 的组合将是未来前列腺癌治疗的有效方法,尤其是对 AR 阳性去势抵抗性前列腺癌有效。
更新日期:2020-10-06
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