title: Inhibition of DNA methyltransferase or histone deacetylase protects retinal pigment epithelial cells from DNA damage induced by oxidative stress by the stimulation of antioxidant enzymes.
abstract: Epigenetic modifications influence DNA damage response (DDR). In this study we explored the role of DNA methylation and histone acetylation in DDR in cells challenged with acute or chronic oxidative stress. We used retinal pigment epithelial cells (ARPE-19), which natively are exposed to oxidative stress due to permanent exposure to light and high blood flow. We employed a DNA methyltransferase inhibitor - RG108 (RG), or a histone deacetylase inhibitor - valproic acid (VA). ARPE-19 cells were exposed to tert-butyl hydroperoxide, an acute oxidative stress inducer, or glucose oxidase, which slowly liberates low-doses of hydrogen peroxide in the presence of glucose, creating chronic conditions. VA and RG reduced level of intracellular reactive oxygen species and DNA damage in ARPE-19 cells in normal condition and in oxidative stress. This protective effect of VA and RG was associated with the up-regulated expression of antioxidant enzyme genes: CAT, GPx1, GPx4, SOD1 and SOD2. RG decreased the number of cells in G2/M checkpoint in response to chronic oxidative stress. Neither RG nor VA changed the DNA repair or apoptosis induced by oxidative stress. Therefore, certain epigenetic manipulations may protect ARPE-19 cells from detrimental effects of oxidative stress by modulation of antioxidative enzyme gene expression, which may be further explored in pharmacological studies on oxidative stress-related eye diseases.
authors.affiliation: Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland. Electronic address: ptokarz@biol.uni.lodz.pl.
authors.forename: Paulina
authors.initials: P
authors.lastname: Tokarz
authors.affiliation: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland. Electronic address: Kai.Kaarniranta@kuh.fi.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.affiliation: Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland. Electronic address: jblasiak@biol.uni.lodz.pl.
authors.forename: Janusz
authors.initials: J
authors.lastname: Blasiak
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010797:Phthalimides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013997:Time Factors; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D056572:Histone Deacetylase Inhibitors; D010797:Phthalimides; C503639:RG108; D017382:Reactive Oxygen Species; D014635:Valproic Acid; D014364:Tryptophan; D004248:DNA (Cytosine-5-)-Methyltransferases; D006655:Histone Deacetylases
keywords: ARPE-19; DNA damage response; Epigenetic inhibitors; Oxidative stress; RG108 (PubChem CID: 702558); Reactive oxygen species; Tert-butyl hydroperoxide (PubChem CID: 6410); Valproic acid (PubChem CID: 3121)