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Updated: Jan 11, 2026

Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
Integration and Intersection of Cancer Metabolism with Epigenetic Pathways in Gliomas
Siva Kumar Natarajan1,2, Matthew Pun1,2,3, James Haggerty-Skeans1,2,3
1Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA;
Abstract:
The interplay between metabolomics and epigenetics is a key glioma driver. Both tumor-intrinsic and microenvironmental metabolic cues can shape chromatin. Epigenetic methylation and demethylation are metabolically regulated by S-adenosyl methionine (SAM) (via methionine metabolism) and the TCA-cycle-related metabolite α-ketoglutarate (α-KG), respectively. Additionally, glycolysis and the TCA cycle modulate histone acetylation and lactylation. Gliomas in both adults and children hijack these pathways. Adult isocitrate dehydrogenase (IDH)-wild-type tumors enhance glycolysis via epidermal growth factor receptor to alter chromatin. IDH-mutant gliomas generate D-2-hydroxyglutarate (D-2HG), which inhibits α-KG demeth-ylases to create epigenetic hypermethylation. Pediatric gliomas, including gliomas with lysine-to-methionine mutations at residue 27 of histone H3 and posterior fossa group A ependymomas, can also rewire metabolism to regulate chromatin. These pathways can be targeted for therapeutic development. Inhibiting IDH mutations with vorasidenib lowers D-2HG and is beneficial to patients. Other drugs like ONC201 and metformin can metabolically suppress oncogenic chromatin states in pediatric gliomas. This dynamic cross talk between metabolism and epigenetics not only underpins tumor biology but also presents opportunities for innovative therapeutic strategies.
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