Department of Urology, Dongtai City People's Hospital, Dongtai, Jiangsu, China.
Department of Urology, Dongtai Hospital, the Affiliated Hospital of Jiangsu Vocational College of Medicine, Dongtai, Jiangsu, China.
Environ Toxicol. 2024 Jun;39(6):3734-3745. doi: 10.1002/tox.24187. Epub 2024 Mar 28.
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.
Docetaxel（DTX）耐药的发展损害了其治疗效果，恶化了前列腺癌（PCa）的预后，而其潜在的调节机制仍知之甚少。在这项研究中，发现在 DTX 耐药的 PCa 细胞和在 DTX 治疗期间表现出疾病进展的 PCa 组织中，METTL14 上调。此外，METTL14 的过表达促进了体外和体内对 DTX 的耐药性发展。有趣的是，观察到 DTX 耐药的 PCa 细胞中 E2F1 靶向位点的超甲基化阻碍了 E2F1 与 METTL14 启动子区域的结合能力，从而增强了其转录活性。因此，METTL14 的这种高表达水平促进了 pri-miR-129 的 m6A 依赖性加工，随后导致 miR-129-5p 的表达增加。我们的研究强调了 E2F1-METTL14-miR-129-5p 轴在调节 PCa 中 DTX 耐药性方面的关键作用，突显了 METTL14 作为 DTX 耐药性 PCa 患者有希望的治疗靶点。
