PRMT5 Methylates and Stabilizes EphA2 via Inhibiting Its Ubiquitination and Degradation to Promote Nasopharyngeal Carcinoma Stem Cell Properties

ABSTRACT Both PRMT5 and EphA2 proteins are overexpressed and play a crucial role in multiple cancers, and have been used as targets to develop new anticancer drugs. However, the function and significance of the PRMT5–EphA2 interaction are unclear. Here, we report that PRMT5 bound to EphA2, catalyzed the dimethylation of EphA2 at arginine 816, and then stabilized EphA2 via inhibiting Cbl‐mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC) cells. Functionally, PRMT5 promoted in vitro and in vivo NPC stem cell properties by methylating and stabilizing EphA2. Based on the interacting regions of PRMT5 and EphA2 proteins, we developed a 20 amino acid‐long PRMT5‐derived peptide, P20, which disrupted the connection of PRMT5 with EphA2, degraded EphA2, and suppressed NPC stem cell properties in vitro and in mice. Moreover, the expression levels of PRMT5 and EphA2 in the NPC tissues were significantly higher than those in the normal nasopharyngeal mucosal tissues, and both proteins for predicting the patient's prognosis are superior to individual proteins. Our findings suggest that PRMT5 methylates and stabilizes EphA2 to promote NPC stem cell properties, and the PRMT5‐derived peptide P20 can serve as a novel strategy for targeting EphA2 degradation and inhibiting NPC stem cell properties.