Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of β-catenin, thereby inducing Wnt/β-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/β-catenin signaling, greatly sensitized GSCs to radiation. Taken together, our results showed that LINC00839, modified by METTL3-mediated m6A, exerts tumor progression and radiation resistance by activating Wnt/β-catenin signaling.
Radiotherapy is a major component of standard-of-care treatment for gliomas, the most prevalent type of brain tumor. However, resistance to radiotherapy remains a major concern. Identification of mechanisms governing radioresistance in gliomas could reveal improved therapeutic strategies for treating patients. Here, we report that mitochondrial metabolic pathways are suppressed in radioresistant gliomas through integrated analyses of transcriptomic data from glioma specimens and cell lines. Decreased expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), the key regulator of mitochondrial biogenesis and metabolism, correlated with glioma recurrence and predicted poor prognosis and response to radiation therapy of glioma patients. The subpopulation of glioma cells with low-mitochondrial-mass exhibited reduced expression of PGC-1α and enhanced resistance to radiation treatment. Mechanistically, PGC-1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase (DNA-PK) in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC-1α by facilitating its binding to the E3 ligase RNF34. Restoring PGC-1α activity with expression of PGC-1α S636A, a phosphorylation-resistant mutant, or a small molecule PGC-1α activator ZLN005 increased radiosensitivity of resistant glioma cells by reactivating mitochondria-related ROS production and inducing apoptotic effects both in vitro and in vivo. In summary, this study identified a self-protective mechanism in glioma cells in which radiation-induced degradation of PGC-1α and suppression of mitochondrial biogenesis play a central role. Targeted activation of PGC-1α could help improve response to radiation therapy in glioma patients.
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