Metabolic Modulation of Epigenetics in Gliomas

Cancer metabolism and epigenetics are two relatively new areas of cancer research. Recent years have seen an explosion of studies implicating either altered tumor metabolism or epigenetic mechanisms in the pathogenesis or maintenance of brain tumors. A new paradigm is emerging in cancer biology that represents a convergence of these themes, the metabolic regulation of epigenetics. We discuss this interrelationship in the context of two metabolic enzymes that can influence the pathogenesis of gliomas by altering the epigenetic state. The first of these enzymes is isocitrate dehydrogenase 1 (IDH1), which is mutated in secondary glioblastomas and approximate to 70% of grade II/III astrocytomas and oligodendrogliomas. Mutant IDH1 results in the production of a metabolite 2-hydroxyglutarate (2-HG) that can inhibit DNA and histone demethylating enzymes resulting in the glioma-CpG island phenotype (G-CIMP) and increased histone methylation marks. Pyruvate kinase M2 (PKM2), an enzyme that plays a critical role in the glycolytic pathway, is a second example of a metabolic enzyme that can affect histone modifications. In epidermal growth factor receptor (EGFR)-driven glioblastoma, PKM2 translocates to the nucleus and phosphorylates histone 3 at threonine 11 (H3-T11). This causes dissociation of HDAC3 from the CCND1 (Cyclin D1) and c-MYC promoters and subsequent histone acetylation, leading to transcription of Cyclin-D1 and c-MYC, and subsequent cell proliferation. Modification of the epigenetic state by alterations in metabolic enzymes is a novel phenomenon that contributes to the pathogenesis of gliomas and may help in the identification of new therapeutic targets.