Brain Tumor Res Treat.  2023 Apr;11(2):86-93. 10.14791/btrt.2023.0011.

Epigenetic and Metabolic Changes in Diffuse Intrinsic Pontine Glioma

• Park J
• Chung C

• KMID: 2542080
• DOI: http://doi.org/10.14791/btrt.2023.0011

Abstract

Diffuse midline glioma (DMG), hitherto known as diffuse intrinsic pontine glioma (DIPG), is a rare and aggressive form of brain cancer that primarily affects children. Although the exact cause of DMG/DIPG is not known, a large proportion of DMG/DIPG tumors harbor mutations in the gene encoding the histone H3 protein, specifically the H3K27M mutation. This mutation decreases the level of H3K27me3, a histone modification that plays a vital role in regulating gene expression through epigenetic regulation. The mutation also alters the function of polycomb repressive complex 2 (PRC2), thereby preventing the repression of genes associated with cancer development. The decrease in H3K27me3 caused by the histone H3 mutation is accompanied by an increase in the level of H3K27ac, a post-translational modification related to active transcription. Dysregulation of histone modification markedly affects gene expression, contributing to cancer development and progression by promoting uncontrolled cell proliferation, tumor growth, and metabolism. DMG/DIPG alters the metabolism of methionine and the tricarboxylic acid cycle, as well as glucose and glutamine uptake. The role of epigenetic and metabolic changes in the development of DMG/DIPG has been studied extensively, and understanding these changes is critical to developing therapies targeting these pathways. Studies are currently underway to identify new therapeutic targets for DMG/DIPG, which may lead to the development of effective treatments for this devastating disease.

Keyword

Epigenomics; Metabolomics; Therapeutics; Diffuse intrinsic pontine glioma; Histone code; Diffuse midline glioma

Figure

• 

  Fig. 1 Illustration of epigenetic regulation. In normal cells, the polycomb repressive complex 2 (PRC2) protein complex adds a methyl group to the H3 protein at specific locations, including H3K27. However, in diffuse intrinsic pontine glioma, mutations in the H3.1 or H3.3 genes result in H3K27 hypomethylation by inhibiting PRC2, leading to a more accessible chromatin state characterized by H3K27 acetylation. KDM6 is an enzyme that removes methylation from H3K27, reducing the H3K27me3 level. Also, histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two enzyme classes that respectively add and remove the acetyl group on histone lysine residue. Acetylated lysine residues on histones recruit bromodomain-containing proteins (BRDs), which activate transcription by recruiting RNA polymerase II (Pol II). Dysregulation of gene expression mediated by histone modification ultimately promotes the development and progression of cancer.

• 

  Fig. 2 Landscape of metabolomic reprogramming by H3K27M. Heatmap illustrates the change of metabolite in H3.3K27M-expressing murine glial cells from Miyai et al. 2020 [36]. Each metabolite level in H3K27M was normalized to wild-type (WT) level. Metabolites (p<0.05) are selected.

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