Temozolomide (TMZ) resistance is a major cause of recurrence and poor prognosis in glioblastoma (GBM). Recently, increasing evidences suggested that long noncoding RNAs (LncRNAs) modulate GBM biological processes, especially in resistance to chemotherapy, but their role in TMZ chemoresistance has not been fully illuminated. Here, we found that LncRNA SOX2OT was increased in TMZ-resistant cells and recurrent GBM patient samples, and abnormal expression was correlated with high risk of relapse and poor prognosis. Knockdown of SOX2OT suppressed cell proliferation, facilitated cell apoptosis, and enhanced TMZ sensitivity. In addition, we identified that SOX2OT regulated TMZ sensitivity by increasing SOX2 expression and further activating the Wnt5a/β-catenin signaling pathway in vitro and in vivo. Mechanistically, further investigation revealed that SOX2OT recruited ALKBH5, which binds with SOX2, demethylating the SOX2 transcript, leading to enhanced SOX2 expression. Together, these results demonstrated that LncRNA SOX2OT inhibited cell apoptosis, promoted cell proliferation, and TMZ resistance by upregulating SOX2 expression, which activated the Wnt5a/β-catenin signaling pathway. Our findings indicate that LncRNA SOX2OT may serve as a novel biomarker for GBM prognosis and act as a therapeutic target for TMZ treatment.

N6-methylation of adenosine (m6A) is one of the most frequent chemical modifications in eukaryotic RNAs and plays a vital role in tumorigenesis and progression. Recently, emerging studies have shown that m6A modification by ALKBH5 was associated with immunotherapy response in various types of cancer. However, whether m6A demethylases ALKBH5 participate in regulating the tumor immune microenvironment and the efficacy of immunotherapy in glioblastoma remain unknown. Here, we found that deletion of ALKBH5 significantly inhibited the growth of glioma allografts, rescued the antitumoral immune response, and increased cytotoxic lymphocyte infiltration and proinflammatory cytokines in CSF while significantly suppressing PD-L1 protein expression. m6A-methylated RNA immunoprecipitation sequencing and RNA sequencing identify ZDDHC3 as the direct target of ALKBH5. Mechanically, ALKBH5 deficiency impairs the YTHDF2-mediated stability of ZDHHC3 mRNA, thereby suppressing PD-L1 expression by accelerating PD-L1 degradation in glioma. In addition, genetic deletion or pharmacological inhibition of ALKBH5 with IOX1 enhances the therapeutic efficacy of anti-PD-1 treatment in preclinical mice models. These data suggest that the combination of anti-PD-1 therapy and ALKBH5 inhibition may be a promising treatment strategy in glioma.

Glioma is a common intracranial malignant tumor with high mortality and high recurrence rate. In recent years, increasing evidence has demonstrated that circular RNAs (circRNAs) are potential biomarkers and therapeutic targets for many tumors. However, the role of circRNAs in glioma remains unclear. In this study, we found that circRNA-0002109 was highly expressed in glioma tissues and cell lines. Downregulation of circRNA-0002109 expression inhibited the proliferation, migration, and invasion of glioma cells and inhibited the malignant progression of tumors in vivo . Investigations into the relevant mechanisms showed that circRNA-0002109 upregulated the expression of EMP2 through endogenous competitive binding of microRNA-129-5P (miR-129-5P), which partially alleviated the inhibitory effect of miR-129-5P on epithelial membrane protein-2 (EMP2) and ultimately promoted the malignant development of glioma. Our results indicate that circRNA-0002109 plays an important role in the proliferation, invasion, and migration of glioma cells by regulating the miR-129-5P/EMP2 axis, which provides a new potential therapeutic target for glioma.