Downregulation of EZH2 inhibits epithelial–mesenchymal transition in enzalutamide-resistant prostate cancer

Zhuangzhuang Zhang, Xinyi Wang, Miyeong Kim, Daheng He, Chi Wang, Ka Wing Fong, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Androgen signaling inhibitors (ASI) have been approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the limited success of ASI in clinic justifies an urgent need to identify new targets and develop novel approaches for treatment. EZH2 significantly increases in prostate cancer (PCa). Little is understood, however, regarding the roles of EZH2 in Enzalutamide-resistant (EnzR) mCRPC. Methods: We firstly investigated the levels of EZH2 and the altered pathways in public database which was comprised with primary and metastatic PCa patient tumors. To elucidate the roles of EZH2 in mCRPC, we manipulated EZH2 in EnzR PCa cell lines to examine epithelial-mesenchymal transition (EMT). To dissect the underlying mechanisms, we measured the transcription levels of EMT-associated transcription factors (TFs). Results: We found that EZH2 was highly expressed in mCRPC than that of primary PCa tumors and that EnzR PCa cells gained more EMT characteristics than those of enzalutamide-sensitive counterparts. Further, loss of EZH2-induced inhibition of EMT is independent of polycomb repressive complex 2 (PRC2). Mechanistically, downregulation of EZH2 inhibits transcription of EMT-associated TFs by repressing formation of H3K4me3 to the promotor regions of the TFs. Conclusion: We identified the novel roles of EZH2 in EnzR mCRPC. EnzR PCa gains more EMT properties than that of enzalutamide-sensitive PCa. Loss of EZH2-assocaited inhibition of EMT is PRC2 independent. Downregulation of EZH2 suppresses EMT by impairing formation of H3K4me3 at the promotor regions, thus repressing expression of EMT-associated TFs.

Original languageEnglish
Pages (from-to)1458-1469
Number of pages12
JournalProstate
Volume83
Issue number15
DOIs
StatePublished - Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 Wiley Periodicals LLC.

Keywords

  • EMT
  • EZH2
  • H3K4me3
  • enzalutamide-resistance
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

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