Blockade of radio-adaptive EZH2-mTOR signaling restores glioblastoma radiosensitivity

Abstract Background Radiotherapy is a commonly utilized treatment modality for glioblastoma but its efficacy remains limited. Recent studies have highlighted the significant role of EZH2 in glioblastoma malignancy. Nonetheless, the contribution of EZH2 to radiotherapy resistance in glioblastoma is not well understood. This study aims to investigate the regulatory mechanisms of EZH2 and its histone methylation substrate H3K27me 3 , as well as their roles in modulating the sensitivity of glioblastoma to radiotherapy. Results Interestingly, the EZH2 inhibitors were found to sensitize GL261 glioblastoma to radiotherapy both in vitro and in vivo . The underlying molecular mechanism involves irradiation-induced stabilization of EZH2, resulting in increased protein levels due to inhibition of its ubiquitination and degradation, which subsequently leads to elevated levels of H3K27me 3 . H3K27me 3 inhibits DEPTOR expression through increased occupancy at its promoter, thereby activating the mTOR signaling. Moreover, the irradiation-induced activation of the mTOR signaling pathway in glioblastoma can be further suppressed by EZH2 inhibitors, leading to a reduction in glioblastoma malignancy. Conclusions EZH2 inhibitors may enhance glioblastoma sensitivity to irradiation by modulating the EZH2-H3K27me 3 -DEPTOR-mTOR signaling axis. The combination of EZH2 inhibitors with radiotherapy presents a promising therapeutic strategy for the treatment of glioblastoma.