“…To understand the biology of these dysregulated metabolites, we performed metabolic pathway enrichment analysis and found enrichment of pyrimidine and methionine metabolism in DMG-H3K27M tumors (blue bars), consistent with recent reports of the importance of these pathways in H3K27M tumors, as well as purine metabolism (Fig. 1 B) [ 25 , 26 , 30 ]. Fig.…”
Background
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain.
Methods
We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT.
Results
DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo.
Conclusions
Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.
“…To understand the biology of these dysregulated metabolites, we performed metabolic pathway enrichment analysis and found enrichment of pyrimidine and methionine metabolism in DMG-H3K27M tumors (blue bars), consistent with recent reports of the importance of these pathways in H3K27M tumors, as well as purine metabolism (Fig. 1 B) [ 25 , 26 , 30 ]. Fig.…”
Background
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain.
Methods
We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT.
Results
DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo.
Conclusions
Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.
“…Inhibition of MAT2A significantly inhibited tumor growth and improved survival in mice with DMGs, whose life expectancy was increased by nearly 50% on a methionine-restricted diet. These results suggest that methionine restriction and MAT2A inhibition are potential treatments for diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG) with H3K27 M mutation …”
Section: Mat2a Biology
and Its Relation To Cancermentioning
Methionine adenosyltransferase 2A
(MAT2A) is a rate-limiting enzyme
in the methionine cycle that primarily catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine
triphosphate (ATP). MAT2A has
been recognized as a therapeutic target for the treatment of cancers.
Recently, a few MAT2A inhibitors have been reported, and three entered
clinical trials to treat solid tumorsor lymphoma with MTAP loss. This review aims to summarize the current understanding of
the roles of MAT2A in cancer and the discovery of MAT2A inhibitors.
Furthermore, a perspective on the use of MAT2A inhibitors for the
treatment of cancer is also discussed. We hope to provide guidance
for future drug design and optimization via analysis of the binding
modes of known MAT2A inhibitors.
“…Other metabolic changes in DMG/DIPG have been reported. Because DMG/DIPG cells show a high dependence on methionine, silencing methionine adenosyltransferase 2A ( MAT2A ) or restricting methionine availability is a potential therapeutic strategy, leading to a change in the epigenome and transcriptome [ 41 ]. The metabolic changes in DMG/DIPG were summarized in Table 1 .…”
Section: Dmg/dipg and Metabolismmentioning
confidence: 99%
“…A recent in vivo study showed that depleting MAT2A or methionine restriction could impede the growth of DMG/DIPG tumors. This suggests that DMG/DIPG tumors have a high dependency on methionine, and that targeting the methionine cycle could be a promising strategy for the treatment of this type of cancer [ 41 ].…”
Section: Treatment By Epigenetic or Metabolomic Regulationmentioning
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.
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