Targeting DNMTs to Overcome Enzalutamide Resistance in Prostate Cancer

Elia Farah, Zhuangzhuang Zhang, Sagar M. Utturkar, Jinpeng Liu, Timothy L. Ratliff, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is an FDA-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period to enzalutamide, tumors will develop drug resistance. In this study, we uncovered that DNA methylation was deregulated in enzalutamide-resistant cells. DNMT activity and DNMT3B expression were upregulated in resistant cell lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in prostate cancer cells with a potential role of p53 and pRB in this process. The overexpression of DNMT3B3, a DNMT3B variant, promoted an enzalutamide-resistant phenotype in C4-2B cell lines. Inhibition of DNA methylation and DNMT3B knockdown induced a resensitization to enzalutamide. Decitabine treatment in enzalutamide-resistant cells induced a decrease of the expression of AR-V7 and changes of genes for apoptosis, DNA repair, and mRNA splicing. Combination treatment of decitabine and enzalutamide induced a decrease of tumor weight, Ki-67 and AR-V7 expression and an increase of cleaved-caspase3 levels in 22Rv1 xenografts. The collective results suggest that DNA methylation pathway is deregulated after enzalutamide resistance onset and that targeting DNA methyltransferases restores the sensitivity to enzalutamide in prostate cancer cells.

Original languageEnglish
Pages (from-to)193-205
Number of pages13
JournalMolecular Cancer Therapeutics
Volume21
Issue number1
DOIs
StatePublished - Jan 2022

Bibliographical note

Funding Information:
This work was funded by NIH R01 CA157429, R01 CA192894, R01 CA196835, and R01 CA196634 (to X. Liu). This research was also supported by the University of Kentucky Markey Cancer Center (P30CA177558). We also acknowledge the Collaborative core for cancer bioinformatics (C3B), Walther Grant, and Purdue Center for Cancer Research for their contribution to the RNA-seq data analysis The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
2021 American Association for Cancer Research

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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