Glutamate dehydrogenase 1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism

BACKGROUND: Glutamine is an important nutrient for cancer cell growth that provides biological sources for nucleic acid and fatty acid synthesis, but the role of glutaminolysis in signal transduction and glioblastoma (GBM) progression remains little known. METHODS: Knockdown and overexpression cells were obtained to explore the functional roles of glutamate dehydrogenase 1 (GDH1) in cell proliferation, tumor formation, and aerobic glycolysis. RNA-seq, Chromatin immunoprecipitation, luciferase assay, and western blot were performed to verify the regulation of the EGFR-AKT pathway by the GDH1 (also known as GLUD1) and KDM6A. Metabolite-level measurements and Seahorse Assay were performed to assess the functional role of GHD1 in reprogramming glycolysis. RESULTS: Here, we report that GDH1 catalytic glutaminolysis is essential for GBM cell line proliferation and brain tumorigenesis even in high-glucose conditions. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate (α-KG). We demonstrate that glutamine in combination with leucine activates mammalian TORC1 by enhancing glutaminolysis and α-KG production. α-KG increases the transcription of PDPK1 by reducing the suppressive histone modification H3K27me3 and then promotes the activation of the PI3K/AKT/mTOR pathway. This transcriptional activation induced by α-KG requires histone demethylase KDM6A, which is a 2-oxoglutarate oxygenase that plays an important role in converting α-KG to succinate. Furthermore, we show that GDH1-catalytic glutaminolysis also increases the expression of HK2 and promotes glycolysis in high-glucose conditions dependent on KDM6A-mediated demethylation of H3K27. CONCLUSIONS: These findings suggest a novel function of glutaminolysis in the regulation of signal transduction and metabolism reprogramming and provide further evidence for the unique role of glutaminolysis in GBM progression.