BRD7 enhances the radiosensitivity of nasopharyngeal carcinoma cells by negatively regulating USP5/METTL3 axis-mediated homologous recombination repair
Mengna Li, Jianxia Wei, Changning Xue, Shipeng Chen, Xiangting Zhou, Lemei Zheng, Yumei Duan, Hongyu Deng, Songqing Fan, Wei Xiong, Faqing Tang, Ming Zhou
Abstract
An important reason for the poor prognosis of nasopharyngeal carcinoma (NPC) patients is radioresistance. Our previous studies demonstrated that BRD7 is expressed at low levels in NPC and functions as a tumor suppressor to inhibit NPC progression and metastasis. However, the role and mechanism of BRD7 in the development of radioresistance in NPC cells remain unclear. In this study, we first found that BRD7 was lowly expressed in radioresistant NPC tissues and cells compared to radiosensitive tissues and cells and that overexpression of BRD7 promoted the induction of DNA double-strand breaks and increased radiosensitivity in NPC cells. Mechanistically, BRD7 competitively inhibits the binding of the deubiquitinating enzyme USP5 to METTL3, thereby reducing the protein stability of METTL3 through the ubiquitin-proteasome pathway. Furthermore, METTL3 was confirmed to suppress the induction of DSBs and promote the development of NPC radioresistance by regulating BRCA1- and RAD51-mediated homologous recombination repair. Moreover, high BRD7 expression and low METTL3 expression are positively correlated with radiosensitivity and good prognosis in NPC patients. Taken together, our findings reveal that BRD7 promotes the radiosensitization of NPC cells by negatively regulating USP5/METTL3 axis activity and indicate that targeting the BRD7/METTL3 axis might be a novel therapeutic strategy for NPC radiosensitization.