NAT10-mediated N4-acetylcytidine (ac4C) modification of PIK3R2 mRNA promotes malignant progression of glioblastoma

Glioma is the most common primary tumor in the central nervous system, with glioblastoma (GBM) representing one of the most malignant forms, accounting for 46.1% of cases. GBM is characterized by rapid progression, high malignancy, and poor prognosis, with median survival remaining less than 15 months despite combined surgery, radiotherapy, and chemotherapy. NAT10, the only known acetyltransferase mediating N4-acetylcytidine (ac4C) modification in eukaryotes, has been implicated in promoting tumorigenesis and progression in colon cancer, bladder cancer, pancreatic ductal cancer, among others. In this study, we found that NAT10 is highly expressed in GBM and is positively correlated with malignant pathological features and poor prognosis in patients. In vitro experiments demonstrated that NAT10 promotes tumor proliferation, migration, and invasion. In vivo experiments further confirmed that NAT10 facilitates malignant progression of tumors. Mechanistically, we revealed that NAT10 regulates PIK3R2 stabilization through ac4C modification, thereby participating malignant characterization of GBM. Additionally, our data demonstrated a positive correlation between NAT10 and PIK3R2 in glioma patients. Taken together, our findings strongly suggest that NAT10 is a potential therapeutic target for GBM.