miR-27b and miR-34a enhance docetaxel sensitivity of prostate cancer cells through inhibiting epithelial-to-mesenchymal transition by targeting ZEB1

Abstract

Docetaxel resistance is a primary clinical obstacle in the therapy of advanced prostate cancer (PCa). Aberrant expression of miR-27b and miR-34a has been revealed to be implicated in drug resistance of different tumors. Nevertheless, the roles of miR-27b and miR-34a in docetaxel resistance of PCa and their molecular mechanisms are far from being elucidated. In this study, we found that miR-27b and miR-34a were significantly downregulated in docetaxel-resistant PCa cells. Gain-of-function experiments showed that overexpression of miR-27b or miR-34a enhanced docetaxel sensitivity and inhibited EMT in docetaxel-resistant PCa cells. Moreover, miR-27b and miR-34a was demonstrated to directly target ZEB1 and suppress ZEB1 expression. Loss-of-function analysis disclosed that ZEB1 knockdown enhanced docetaxel sensitivity and suppressed EMT in docetaxel-resistant PCa cells. Rescue experiments presented that ZEB1 overexpression abolished the effects of miR-27b or miR-34a overexpression on docetaxel sensitivity and EMT in docetaxel-resistant PCa cells. Finally, Tumor xenograft assay confirmed the contribution of miR-27b and miR-34a in improving docetaxel sensitivity in PCa in vivo. In summary, miR-27b and miR-34a overexpression enhanced docetaxel sensitivity of PCa partly through inhibiting EMT by targeting ZEB1, providing new insights into the molecular mechanism of miR-27b and miR-34a in modulating docetaxel resistance and potential therapy targets in advanced PCa.

Keywords: Docetaxel sensitivity; EMT; MiR-27b; Prostate cancer; ZEB1; miR-34a.