Inhibition of O-GlcNAcylation Reduces Cell Viability and Autophagy and Increases Sensitivity to Chemotherapeutic Temozolomide in Glioblastoma

SIMPLE SUMMARY: Glioblastoma (GB) is the most common and aggressive type of malignant brain tumor; however, despite advances in treatment modalities, it remains largely incurable. Current therapeutic protocols are ineffective, and temozolomide (TMZ), the main chemotherapy used in GB treatment, has a high resistance rate. Aberrant O-GlcNAcylation is related to the tumorigenesis of several tumor types, and targeting O-GlcNAc transferase (OGT) is a possible therapeutic target for some tumor types. Here, we investigated the effect of OGT inhibition on cellular proliferation, cell death, and autophagy, as well as whether it could improve the effect of TMZ on cell viability. Our findings indicated that targeting OGT shows promising potential as a therapeutic strategy for treating GB. ABSTRACT: Glioblastoma (GB) is the most aggressive primary malignant brain tumor and is associated with short survival. O-GlcNAcylation is an intracellular glycosylation that regulates protein function, enzymatic activity, protein stability, and subcellular localization. Aberrant O-GlcNAcylation is related to the tumorigenesis of different tumors, and mounting evidence supports O-GlcNAc transferase (OGT) as a potential therapeutic target. Here, we used two human GB cell lines alongside primary human astrocytes as a non-tumoral control to investigate the role of O-GlcNAcylation in cell proliferation, cell cycle, autophagy, and cell death. We observed that hyper O-GlcNAcylation promoted increased cellular proliferation, independent of alterations in the cell cycle, through the activation of autophagy. On the other hand, hypo O-GlcNAcylation inhibited autophagy, promoted cell death by apoptosis, and reduced cell proliferation. In addition, the decrease in O-GlcNAcylation sensitized GB cells to the chemotherapeutic temozolomide (TMZ) without affecting human astrocytes. Combined, these results indicated a role for O-GlcNAcylation in governing cell proliferation, autophagy, cell death, and TMZ response, thereby indicating possible therapeutic implications for treating GB. These findings pave the way for further research and the development of novel treatment approaches which may contribute to improved outcomes and increased survival rates for patients facing this challenging disease.