USP5 Binds and Stabilizes EphA2 to Increase Nasopharyngeal Carcinoma Radioresistance

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment. However, the underlying mechanism of NPC radioresistance remains poorly understood, and the promising radiosensitizer for NPC radiotherapy is also lacked. Overexpression of USP5 and EphA2 has been linked to various cancers, and both the proteins have attracted considerable attention for the development of new anti-cancer drugs. Here, we report that USP5 interacts with EphA2, and increases EphA2 protein stability and expression by ubiquitin proteasome pathway in the NPC cells. Mebendazole (MBZ), a broad-spectrum anthelmintic drug, transcriptionally inhibits USP5 expression, and then promotes EphA2 ubiquitination degradation in the NPC cells. Functionally, USP5 enhances in vitro and in vivo NPC cell radioresistance via stabilizing EphA2, and MBZ decreases in vitro and in vivo NPC cell radioresistance via targeting USP5/EphA2 axis. Moreover, the levels of USP5 and EphA2 are significantly higher in the radioresistant NPCs than those in the radiosensitive NPCs, and both proteins for predicting patient prognosis are superior to individual protein. These findings suggest that USP5 binds and stabilizes EphA2 by ubiquitin proteasome pathway to promote NPC radioresistance, and MBZ increases NPC radiosensitivity by targeting USP5/EphA2 axis, and is a potential radiosensitizer in NPC and perhaps in other cancers.