Neuro-Oncology | GDH1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism

This study reveals that GDH1-catalytic glutaminolysis promotes GBM cell proliferation and brain tumor development even under high-glucose conditions, and identifies a KDM6A-dependent histone H3K27me3 demethylation mechanism that regulates PDPK1 and HK2 transcription, thereby activating the EGFR/PI3K/AKT signaling pathway and reprogramming glycolysis. These findings provide new insights for targeted therapies.

 

Literature Overview
The article 'GDH1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism', published in Neuro-Oncology, systematically reviews the role of glutamate dehydrogenase 1 (GDH1) in glioblastoma (GBM) signal transduction and metabolic reprogramming. Using RNA-seq, chromatin immunoprecipitation, dual-luciferase reporter assays, and Seahorse analyses, the study comprehensively explores the dual functions of glutamine metabolism in GBM progression: serving not only as an energy metabolic intermediate but also as a precursor for α-KG-mediated histone demethylation. The work further uncovers the molecular mechanism by which GDH1 collaborates with KDM6A to regulate the EGFR-AKT signaling axis and glycolytic gene expression, establishing novel metabolic therapeutic targets for GBM.

Background Knowledge
Glioblastoma (GBM) represents the most aggressive and heterogeneous malignant tumor in the central nervous system, characterized by poor prognosis and lack of effective targeted therapies. While glutamine metabolism typically serves as an alternative energy source to glucose in cancer cells, supporting TCA cycle and bioenergetics under low-glucose conditions, this study demonstrates for the first time that GDH1-mediated glutaminolysis remains critical for GBM cell survival and tumor development even under high-glucose environments. The work focuses on the interplay between α-KG (a glutamine metabolite) and histone modification H3K27me3, particularly KDM6A's role as an α-KG-dependent histone demethylase. Through gene silencing, overexpression experiments, metabolite supplementation, and histone modification analyses, the research team discovered that GDH1 enhances EGFR-AKT-mTOR signaling by increasing α-KG production, reducing H3K27me3 levels, and activating PDPK1 transcription. Additionally, GDH1 promotes glycolytic reprogramming through KDM6A-dependent HK2 upregulation. This mechanism establishes novel crosstalk between metabolism, epigenetics, and signaling pathways in GBM, laying the foundation for combination therapies targeting GDH1 or KDM6A.

 

 

Research Methods and Experiments
The research team constructed GBM cell lines with GDH1 knockdown and overexpression to evaluate changes in cell proliferation, tumor formation, and glycolytic activity. RNA-seq analysis identified GDH1-regulated signaling pathways, while chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays validated histone modification changes at the PDPK1 promoter region. Intracellular α-KG and succinate levels were quantified using metabolic detection kits, and glycolytic capacity was assessed through ECAR measurements on Seahorse XF analyzers. In animal models, stable GBM cells expressing shNT, shGDH1, or KDM6A knockdown were intracranially implanted into nude mice to monitor tumor growth and survival outcomes. The study also employed KDM6A inhibitor GSK-J4 to evaluate its impact on GDH1-mediated signaling activation.

Key Conclusions and Perspectives

• GDH1-mediated glutaminolysis is essential for GBM cell proliferation and brain tumor development under high-glucose conditions, requiring its dehydrogenase activity
• GDH1 activates EGFR-AKT/mTOR signaling by catalyzing glutamine to α-KG, reducing H3K27me3 levels, and enhancing PDPK1 transcription
• This signaling activation depends on histone demethylase KDM6A, with GDH1 and KDM6A collaboratively regulating H3K27me3 modifications
• Under high-glucose conditions, GDH1 reprograms glycolysis through KDM6A-dependent HK2 upregulation
• KDM6A depletion significantly suppresses GDH1's promotion of EGFR-AKT signaling and HK2 expression
• Signal inhibition and metabolic alterations caused by GDH1 deletion can be reversed by α-KG supplementation or wild-type GDH1 restoration, but not by GDH1 R496S mutant
• This study identifies a novel mechanism where glutaminolysis feedback activates EGFR/AKT signaling and reprograms GBM metabolism, providing theoretical basis for targeting metabolic and epigenetic regulation in combination therapies

Research Significance and Prospects
The study establishes a new paradigm for glutaminolysis in GBM progression under high-glucose conditions, elucidating its regulatory relationship with the EGFR-AKT signaling axis and histone modifications. Future research should explore GDH1 and KDM6A as combined therapeutic targets in GBM, develop small-molecule inhibitors targeting both glutaminolysis and histone demethylation pathways, and investigate whether this mechanism exists broadly in other cancers and its potential correlation with IDH mutation status.

 

 

Conclusion
This study systematically defines the novel roles of glutaminolysis in GBM metabolism and signal transduction. GDH1 enhances EGFR-AKT/mTOR signaling by catalyzing glutamine conversion to α-KG, reducing histone H3K27me3 modification, and activating PDPK1 transcription. Simultaneously, GDH1 collaborates with KDM6A to regulate HK2 expression and drive glycolytic reprogramming. These findings expand our understanding of glutamine metabolism's functions in cancer biology while providing molecular evidence supporting anti-GBM therapeutic strategies targeting GDH1 or KDM6A. Future interventions combining metabolic and epigenetic modulators may yield more effective GBM treatments.

 

Rui Yang, Guanghui Zhang, Zhen Meng, Shanshan Wang, and Hongjuan Cui. Glutamate dehydrogenase 1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism. Neuro-Oncology.