Inhibition of EZH2 enhances the antitumor efficacy of metformin in prostate cancer

Yifan Kong, Yanquan Zhang, Fengyi Mao, Zhuangzhuang Zhang, Zhiguo Li, Ruixin Wang, Jinghui Liu, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2490-2501
Number of pages12
JournalMolecular Cancer Therapeutics
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2020

Bibliographical note

Publisher Copyright:
© 2020 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Inhibition of EZH2 enhances the antitumor efficacy of metformin in prostate cancer'. Together they form a unique fingerprint.

Cite this