Epigenetic activation of METTL14 promotes docetaxel resistance in prostate cancer by promoting pri‐microRNA‐129 maturation

Abstract The development of resistance to Docetaxel (DTX) compromises its therapeutic efficacy and worsens the prognosis of prostate cancer (PCa), while the underlying regulatory mechanism remains poorly understood. In this study, METTL14 was found to be upregulated in DTX‐resistant PCa cells and PCa tissues exhibiting progressive disease during DTX therapy. Furthermore, overexpression of METTL14 promoted the development of resistance to DTX in both in vitro and in vivo. Interestingly, it was observed that the hypermethylation of the E2F1 targeting site within DTX‐resistant PCa cells hindered the binding ability of E2F1 to the promoter region of METTL14, thereby augmenting its transcriptional activity. Consequently, this elevated expression level of METTL14 facilitated m6A‐dependent processing of pri‐miR‐129 and subsequently led to an increase in miR‐129‐5p expression. Our study highlights the crucial role of the E2F1‐METTL14‐miR‐129‐5p axis in modulating DTX resistance in PCa, underscoring METTL14 as a promising therapeutic target for DTX‐resistant PCa patients.