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

18 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.

Funding

This work was funded by NIH R01 CA157429, R01 CA192894, R01 CA196835, and R01 CA196634 (to X. Liu) and the Chinese Scholarship Council (to Y. Kong). This research is also supported by the University of Kentucky Markey Cancer Center (P30CA177558).

FundersFunder number
Chinese Scholarship Council
National Institutes of Health (NIH)R01 CA192894, R01 CA196634, R01 CA157429
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer InstituteR01CA196835
National Childhood Cancer Registry – National Cancer Institute
University of Kentucky Markey Cancer CenterP30CA177558
University of Kentucky Markey Cancer Center

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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