Journal
FRONTIERS IN ONCOLOGY
Volume 7, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2017.00046
Keywords
cobalamin; D-4 dopamine receptor; glioblastoma; Nrf2; DNA methylation; glutathione; methionine synthase; transsulfuration
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Glioblastoma is an exceptionally difficult cancer to treat. Cancer is universally marked by epigenetic changes, which play key roles in sustaining a malignant phenotype, in addition to disease progression and patient survival. Studies have shown strong links between the cellular redox state and epigenetics. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a redox-sensitive transcription factor that upregulates endogenous antioxidant production, and is aberrantly expressed in many cancers, including glioblastoma. Methylation of DNA and histones provides a mode of epigenetic regulation, and cobalamin-dependent reactions link the redox state to methylation. Antagonists of dopamine receptor subtype 4 (D-4 receptor) were recently shown to restrict glioblastoma stem cell growth by downregulating trophic signaling, resulting in inhibition of functional autophagy. In addition to stimulating glioblastoma stem cell growth, D-4 receptors have the unique ability to catalyze cobalamin-dependent phospholipid methylation. Therefore, D4 receptors represent an important node in a molecular reflex pathway involving Nr12 and cobalamin, operating in conjunction with redox status and methyl group donor availability. In this article, we describe the redox-related effects of Nrf2, cobalamin metabolism, and the D-4 receptor on the regulation of the epigenetic state in glioblastoma.
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