PRMT3-mediated arginine methylation of YBX1 promotes tumorigenesis in glioblastoma

Abstract Glioblastoma (GBM) represents one of the most challenging tumor types to treat clinically, characterized by an exceedingly poor patient prognosis. This is primarily attributable to the ambiguous molecular mechanisms that hinder the advancement of targeted therapies. Here, PRMT3 is identified as a key driver of tumorigenesis in GBM. Bioinformatics and clinical data reveal that high expression of PRMT3 in glioma cells is closely correlated with poor patient prognosis. Functional experiments demonstrate that PRMT3 overexpression enhances the proliferative capacity of GBM cells. Mechanistically, PRMT3 interacts with Y-box binding protein 1 (YBX1), and catalyzes the arginine methylation of YBX1 protein at R69 within its cold-shock domain. Subsequently, it was found that methylated YBX1 binds to 5-methylcytosine (m5C)-modified E2F1 mRNA and stabilizes its transcription, significantly promoting the expression of E2F1. The resulting PRMT3-YBX1-E2F1 axis sustains high E2F1 protein levels, activates a proliferation-associated transcriptional program, and is essential for GBM cell proliferation in vitro and in vivo . Meanwhile, the PRMT3 inhibitor SGC707 and the non-methylated YBX1 peptide significantly inhibited the proliferation of GBM cells. Our findings underscore that PRMT3 stabilizes E2F1 transcription through methylation of YBX1 at R69, promoting GBM tumorigenesis, and highlight the PRMT3-YBX1-E2F1 axis as a potential therapeutic target for GBM treatment.