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Epigenetic dysregulation in glioma.

Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K - Cancer Sci. (2014)

Bottom Line: Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation.Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma.In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

View Article: PubMed Central - PubMed

ABSTRACT
Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

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Related in: MedlinePlus

IDH mutations induce G-CIMP. Mutations in IDH1 (a cytoplasmic enzyme) and IDH2 (a mitochondrial enzyme) are found frequently in proneural glioblastoma multiforme (GBM). IDH1 mutations are more common than IDH2 mutations. Mutated IDH1 and IDH2 gain the ability to produce the metabolite, 2-hydroxyglutarate (2-HG), which inhibits α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases and the TET protein family. Therefore, mutation of IDH1 is the mechanistic cause of G-CIMP through inhibition of the TET-mediated production of 5hmC, which is a primary mode of DNA demethylation.
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fig02: IDH mutations induce G-CIMP. Mutations in IDH1 (a cytoplasmic enzyme) and IDH2 (a mitochondrial enzyme) are found frequently in proneural glioblastoma multiforme (GBM). IDH1 mutations are more common than IDH2 mutations. Mutated IDH1 and IDH2 gain the ability to produce the metabolite, 2-hydroxyglutarate (2-HG), which inhibits α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases and the TET protein family. Therefore, mutation of IDH1 is the mechanistic cause of G-CIMP through inhibition of the TET-mediated production of 5hmC, which is a primary mode of DNA demethylation.

Mentions: Mutations in IDH1 have been shown to induce the accumulation of methylated DNA via the inhibition of DNA demethylation (Fig. 2).(18) IDH are NAD+ and NADP+-dependent enzymes that catalyze the third step of the tricarboxylic acid (TCA) cycle, and mutations in IDH1 cause a metabolite called 2-hydroxyglutarate (2-HG) to accumulate.(19) The accumulated 2-HG impairs the activity of ten-eleven translocation (TET) methylcytosine dioxygenase, which results in DNA hypermethylation.(18) This is supported by an in vitro study that demonstrates that the DNA methylation pattern is altered in human astrocytes expressing mutant IDH1 (R132H).(20) Collectively, these data indicate that mutation of IDH1 may result in G-CIMP through inhibition of the TET-mediated production of 5-hydroxymethylcytosine (5hmC), which is a primary mode of DNA demethylation. Although further investigations are required before it can be concluded that impaired TET activity is the major cause of aberrant DNA hypermethylation, these fascinating studies clearly demonstrate a link between an altered metabolite profile owing to the mutation of metabolic genes and an aberrant epigenome associated with cancer.


Epigenetic dysregulation in glioma.

Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K - Cancer Sci. (2014)

IDH mutations induce G-CIMP. Mutations in IDH1 (a cytoplasmic enzyme) and IDH2 (a mitochondrial enzyme) are found frequently in proneural glioblastoma multiforme (GBM). IDH1 mutations are more common than IDH2 mutations. Mutated IDH1 and IDH2 gain the ability to produce the metabolite, 2-hydroxyglutarate (2-HG), which inhibits α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases and the TET protein family. Therefore, mutation of IDH1 is the mechanistic cause of G-CIMP through inhibition of the TET-mediated production of 5hmC, which is a primary mode of DNA demethylation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317798&req=5

fig02: IDH mutations induce G-CIMP. Mutations in IDH1 (a cytoplasmic enzyme) and IDH2 (a mitochondrial enzyme) are found frequently in proneural glioblastoma multiforme (GBM). IDH1 mutations are more common than IDH2 mutations. Mutated IDH1 and IDH2 gain the ability to produce the metabolite, 2-hydroxyglutarate (2-HG), which inhibits α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases and the TET protein family. Therefore, mutation of IDH1 is the mechanistic cause of G-CIMP through inhibition of the TET-mediated production of 5hmC, which is a primary mode of DNA demethylation.
Mentions: Mutations in IDH1 have been shown to induce the accumulation of methylated DNA via the inhibition of DNA demethylation (Fig. 2).(18) IDH are NAD+ and NADP+-dependent enzymes that catalyze the third step of the tricarboxylic acid (TCA) cycle, and mutations in IDH1 cause a metabolite called 2-hydroxyglutarate (2-HG) to accumulate.(19) The accumulated 2-HG impairs the activity of ten-eleven translocation (TET) methylcytosine dioxygenase, which results in DNA hypermethylation.(18) This is supported by an in vitro study that demonstrates that the DNA methylation pattern is altered in human astrocytes expressing mutant IDH1 (R132H).(20) Collectively, these data indicate that mutation of IDH1 may result in G-CIMP through inhibition of the TET-mediated production of 5-hydroxymethylcytosine (5hmC), which is a primary mode of DNA demethylation. Although further investigations are required before it can be concluded that impaired TET activity is the major cause of aberrant DNA hypermethylation, these fascinating studies clearly demonstrate a link between an altered metabolite profile owing to the mutation of metabolic genes and an aberrant epigenome associated with cancer.

Bottom Line: Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation.Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma.In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

View Article: PubMed Central - PubMed

ABSTRACT
Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

Show MeSH
Related in: MedlinePlus