NAT10 promotes prostate cancer progression by acetylating mRNA of MARK2 and activating mTOR/HIF-1α/C-Myc pathway to enhance glycolytic reprogramming.

The dysregulation of mRNA modifications, particularly acetylation of cytidine (ac4C), has emerged as a pivotal mechanism in the context of tumor biology, including prostate cancer (PCa), where its exact role mediated by NAT10 remains ill-defined. This study aimed to elucidate the clinical significance of NAT10 in PCa. Our results indicated a pronounced overexpression of NAT10 in PCa tissues and cell lines, which correlated with enhanced cellular proliferation, migration, invasion, and overall tumor growth. Furthermore, acetylated RNA immunoprecipitation sequencing (acRIP-seq) revealed that NAT10 facilitates ac4C modification of MARK2 mRNA, which was consequentially linked to a decrease in mRNA stability and translational efficiency upon NAT10 knockdown, as validated through western blot analysis. Mechanistic investigations demonstrated that NAT10 elevates MARK2 expression, activating the mTOR/HIF-1α/C-Myc signaling cascade, thereby promoting aerobic glycolysis in PCa cells. Consequently, these findings underscore the crucial role of ac4C mRNA modifications in the progression of PCa and position MARK2 as a significant mediator of metabolic reprogramming, suggesting that targeting ac4C mRNA modifications may provide a novel therapeutic strategy for managing prostate cancer.