IL-5 EPIGENETIC REGULATION IN GLIOMA METABOLISM

Abstract In most cancer cells including glioma cells, glucose is at-least partially metabolized to lactate through the Warburg Effect, which refers to the non-oxidative metabolism of glucose even in the presence of sufficient oxygen. In addition to the advantage conferred upon glioma cells by the canonical glycolysis pathway, through supporting rapid proliferation and survival, its end product, lactate, serves as a key factor to regulate H3K27 acetylation (H3K27ac) through histone deacetylases (HDACs). We and others have shown that increase lactate metabolism related to tumor progression in high-grade gliomas including diffuse midline glioma (DMGs). In the orthotopic DMG patient-derived xenograft models, the levels of lactate were elevated relative to the contralateral normal brain using hyperpolarized carbon-13 (13C) magnetic resonance spectroscopic imaging (MRSI), indicating increase lactate metabolism associated DMG growth. Deregulated glucose metabolism can be therapeutically targeted at different levels, from the master regulators that control glucose metabolism to key enzymes controlling rate-limiting steps in glycolytic pathways. Recent integrate analysis using RNA- and ChIP- sequencing uncovered a novel function of lactate in transcriptional regulation and chromatin machinery, offering a promising avenue for therapeutic exploration. Inhibition of lactate dehydrogenase (LDH), the enzyme involved in lactate production, induced loss of histone H3K27ac and regulated the expression of key morphogenesis genes. The epigenetic dysregulation in DMG harboring histone gene mutation, H3K27M, caused a global reduction of H3K27 methylation. While decreasing K27 methylation, the K27M mutation also causes an increase in H3K27ac, in turn, leads to extensive transcriptional reprogramming of mutant cells. These findings provide the rational for development of novel therapeutic strategies to target lactate-dependent epigenetic regulation in DMG. This new therapeutic approach may benefit not only the patients that are afflicted with highly aggressive brain cancers but also perhaps those afflicted with other cancer subtypes.