Targeting DNMTs to Overcome Enzalutamide Resistance in Prostate Cancer
MOLECULAR CANCER THERAPEUTICS(2022)
摘要
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 resis-tance. 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. Enza-lutamide 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 resensitization to enzalutamide. Decitabine treatment in enzalu-tamide-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 deregu-lated after enzalutamide resistance onset and that targeting DNA methyltransferases restores the sensitivity to enzalutamide in prostate cancer cells.
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要