This study demonstrates that GDH1-catalyzed glutaminolysis promotes GBM cell proliferation and brain tumor progression under high-glucose conditions. It reveals a novel mechanism where GDH1 regulates PDPK1 and HK2 transcription through KDM6A-dependent H3K27me3 histone demethylation, thereby activating the EGFR/PI3K/AKT signaling pathway and reprogramming glycolysis. These findings provide critical insights for developing targeted therapies against GBM.
Literature Overview
This study, published in Neuro-Oncology, systematically investigates the dual roles of glutamate dehydrogenase 1 (GDH1)-catalyzed glutaminolysis in glioblastoma (GBM) signaling and metabolic reprogramming. Using RNA-seq, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, and Seahorse XF analysis, the research uncovers how glutamine metabolism functions not only as an energy source but also as a precursor for α-KG to modulate histone modifications. The study identifies GDH1-KDM6A cooperative regulation of the EGFR-AKT signaling axis and glycolytic gene expression, establishing novel molecular targets for GBM metabolic therapy.
Background Knowledge
Glioblastoma (GBM) is the most aggressive and heterogeneous malignant brain tumor in the central nervous system, with extremely poor prognosis and limited therapeutic options. While glutamine metabolism traditionally compensates for glucose deficiency in cancer cells, this research first reveals that GDH1-mediated glutaminolysis remains essential for GBM survival and tumorigenesis even under high-glucose conditions. The study focuses on the interplay between α-KG (a glutamine metabolite) and histone H3K27me3 modifications, highlighting KDM6A as an α-KG-dependent histone demethylase. Through gene silencing, overexpression, metabolite rescue experiments, and histone modification analysis, the team discovered that GDH1 enhances EGFR-AKT-mTOR signaling by reducing H3K27me3 levels via α-KG production, while also driving glycolytic reprogramming through KDM6A-dependent HK2 upregulation. These findings establish a groundbreaking framework for metabolic-epigenetic crosstalk in GBM and inform combinatorial therapeutic strategies targeting GDH1 or KDM6A.
Research Methods and Experiments
The researchers established GDH1-knockdown and GDH1-overexpression GBM cell lines to evaluate changes in proliferation, tumor formation, and glycolytic activity. RNA-seq identified GDH1-regulated signaling pathways, while ChIP and dual-luciferase assays confirmed histone modification dynamics at the PDPK1 promoter. Metabolite levels of α-KG and succinate were quantified using detection kits, and extracellular acidification rate (ECAR) measurements assessed glycolytic capacity via Seahorse XF analysis. In vivo, stable GBM cells expressing shNT, shGDH1, or KDM6A knockdown were intracranially injected into nude mice to monitor tumor growth and survival. The KDM6A inhibitor GSK-J4 was employed to evaluate its impact on GDH1-mediated pathway activation.
Key Conclusions and Perspectives
Research Significance and Prospects
The study establishes a paradigm-shifting role for glutaminolysis in GBM progression under high-glucose conditions, while elucidating its interplay with the EGFR-AKT signaling axis and histone modifications. Future work should explore GDH1 and KDM6A as synergistic therapeutic targets, develop small-molecule inhibitors that block both glutaminolysis and histone demethylation, and investigate whether this mechanism occurs in other cancers or correlates with IDH mutation status.
Conclusion
This study defines a novel role for glutaminolysis in GBM metabolism and signaling. GDH1 catalyzes glutamine conversion to α-KG, reduces H3K27me3 levels, and activates PDPK1 transcription to enhance EGFR-AKT/mTOR signaling. Concurrently, GDH1 collaborates with KDM6A to upregulate HK2 and drive glycolytic reprogramming. These findings expand the functional understanding of glutaminolysis in cancer metabolism and provide mechanistic evidence supporting therapeutic targeting of GDH1 or KDM6A. Future strategies may combine metabolic and epigenetic inhibitors for improved GBM interventions.
