AUTHOR=Schrier Matthew Scott , Trivedi Malav Suchin , Deth Richard Carlton 

TITLE=Redox-Related Epigenetic Mechanisms in Glioblastoma: Nuclear Factor (Erythroid-Derived 2)-Like 2, Cobalamin, and Dopamine Receptor Subtype 4

JOURNAL=Frontiers in Oncology

VOLUME=7

YEAR=2017

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2017.00046

DOI=10.3389/fonc.2017.00046

ISSN=2234-943X

ABSTRACT=<p>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<sub>4</sub> 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<sub>4</sub> receptors have the unique ability to catalyze cobalamin-dependent phospholipid methylation. Therefore, D<sub>4</sub> receptors represent an important node in a molecular reflex pathway involving Nrf2 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<sub>4</sub> receptor on the regulation of the epigenetic state in glioblastoma.</p>