Dynamic Arginine Methylation of YBX1 Relay Controls Its Phase Separation and Chemoradiotherapy Resistance in Rectal Cancer

Abstract Although neoadjuvant chemoradiotherapy is the standard treatment and significantly improves prognosis of locally advanced rectal cancer, patients may develop primary or secondary therapy resistance. Here, through functional screening, we identify PRMT3 as a key driver of chemoradiotherapy resistance in rectal cancer. PRMT3 induces the arginine methylation of Y‐box binding protein 1 (YBX1), which suppresses YBX1's capacity for phase separation in cytoplasm and is imperative for its nucleus translocation. Subsequently, lysine‐specific demethylase 4A (KDM4A) demethylates YBX1 to unmask the R247 residue and promote its phase separation in the nucleus, which strengthens its ability to transcriptionally regulate expressions of ATP‐binding cassette (ABC) transporters and homologous recombination (HR) repair genes and reinforces chemoradiotherapy resistance. Of particular translational importance, high‐throughput FDA‐approved drugs library screening identifies acipimox as a potent PRMT3 inhibitor and chemoradiotherapy sensitizer. This study offers a tangible prospect for improving therapeutic outcomes in rectal cancer patients in a clinically relevant setting.