Abstract
Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.
Highlights
Gliomas and glioblastomas are brain cancers with significant morbidity and mortality, and limited treatment options
Introduction of the IDH1R132H mutation in astrocytoma cells has been associated with both global histone hypermethylation [84], and enrichment of specific histone methylation marks [85]
These characteristics are driven by the hypoxia inducible factors (HIFs) which are regulated by microenvironmental oxygen levels and the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) enzymes, prolyl hydroxylases (PHD) and factor inhibiting hypoxiainducible factor (HIF) (FIH) (Figure 4) [91]
Summary
Gliomas and glioblastomas are brain cancers with significant morbidity and mortality, and limited treatment options. JMJD3 expression increased in neurons [75], but the modulation of specific histone methylation marks in response to varying oxygen tensions, and ranges of iron and 2-OG levels in brain cells, has yet to be determined.
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