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.
|Number of pages||12|
|Journal||Molecular Cancer Therapeutics|
|State||Published - Dec 1 2020|
Bibliographical noteFunding Information:
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).
© 2020 American Association for Cancer Research.
ASJC Scopus subject areas
- Cancer Research