G6PD drives glioma invasion by regulating SQSTM1 protein stability

Glioma is an incurable brain tumor with high recurrence due to the frequent invasion of neoplastic cells. Glucose-6-phosphate dehydrogenase (G6PD) is a critical enzyme in the pentose phosphate pathway (PPP) whose aberrant expression drives the pathogenesis of various cancers. Recent research has identified other moonlight modes of enzymes besides the well-known regulation of metabolic reprogramming. Here, we identified previously unexplored roles of G6PD in glioma via gene set variation analysis (GSVA) based on the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) database. Furthermore, survival analyses revealed that glioma patients with high G6PD expression had a worse outcome than patients with low G6PD expression (Hazard Ratio (95%CI): 2.96 (2.41, 3.64), p = 3.5E-22). Combined with functional assays, G6PD was shown to be related with the migration and invasion in glioma. G6PD knockdown could inhibit the migration in LN229 cells. And G6PD overexpression enhanced LN229 cell migration and invasion. Mechanically, the knockdown of G6PD reduced sequestosome 1 (SQSTM1) protein stability under cycloheximide (CHX) treatment. Moreover, the overexpression of SQSTM1 rescued the impaired migrated and invasive phenotypes in G6PD-silenced cells. Clinically, we validated the role of G6PD-SQSTM1 axis in glioma prognosis by constructing the multivariate cox proportional hazards regression model. These results define a pivotal function of G6PD in modulating SQSTM1 to promote glioma aggressiveness. And G6PD may be a prognostic biomarker and potential therapeutic target in glioma. G6PD-SQSTM1 axis may be a potential prognostic biomarker in glioma.