METTL3 facilitates renal cell carcinoma progression by PLOD2 m 6 A-methylation under prolonged hypoxia
Cell Death & Disease(2024)
摘要
N6-methyladenosine (m 6 A) is the most prevalent reversible modification in eukaryotic mRNA, and it plays a critical role in tumor progression. The purpose of this study was to investigate the function and regulatory mechanisms of the methyltransferase METTL3 in renal cell carcinoma (RCC). METTL3 expression was upregulated and predicted a poor prognosis in patients with advanced RCC. METTL3 facilitated the proliferation, migration, and invasion of RCC cells, depending on its methylase activity. METTL3 positively regulated the expression of PLOD2, and both genes were triggered under prolonged hypoxia. Mechanistically, hypoxia-induced the binding of HIF-1α to the METTL3 promoter, which enhanced its transcriptional activity. METTL3-mediated m 6 A modifications of PLOD2 mRNA at 3’UTR region, promoting the translation of PLOD2 protein. Furthermore, silencing METTL3 impaired RCC progression in vitro. In vivo, administration of highly potent and selective METTL3 inhibitor STM2457 showed anti-tumor effects, whereas AAV9-mediated re-transduction of PLOD2 largely abolished the above phenomenon in a subcutaneous mouse model. These findings reveal that hypoxia and HIF-driven METTL3 transcription promote RCC progression by increasing PLOD2 expression in an m 6 A-dependent manner, suggesting that METTL3 may serve as a novel pharmaceutical intervention for RCC.
更多查看译文
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要