Inhibition of DNA methylation in proliferating human lymphoma cells by immune cell oxidants

• Published in: The Journal of biological chemistry 2020-06, Vol.295 (23), p.7839-7848
• Main Authors: O'Connor, Karina M., Das, Andrew B., Winterbourn, Christine C., Hampton, Mark B.
• Format: Article
• Language: English
• Subjects: Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chloramines - pharmacology; DNA methylation; DNA Methylation - drug effects; DNA methyltransferase (DNMT); DNA, Neoplasm - drug effects; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; epigenetics; Glycine - analogs & derivatives; Glycine - pharmacology; glycine chloramine; Humans; hydrogen peroxide; inflammation; Jurkat Cells; Lymphoma - drug therapy; Lymphoma - immunology; Lymphoma - pathology; Metabolism; neutrophil; Oxidants - pharmacology; oxidative stress; redox signaling; tumor microenvironment
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA120.013092

Excessive generation of oxidants by immune cells results in acute tissue damage. One mechanism by which oxidant exposure could have long-term effects is modulation of epigenetic pathways. We hypothesized that methylation of newly synthesized DNA in proliferating cells can be altered by oxidants that target DNA methyltransferase activity or deplete its substrate, the methyl donor SAM. To this end, we investigated the effect of two oxidants produced by neutrophils, H2O2 and glycine chloramine, on maintenance DNA methylation in Jurkat T lymphoma cells. Using cell synchronization and MS-based analysis, we measured heavy deoxycytidine isotope incorporation into newly synthesized DNA and observed that a sublethal bolus of glycine chloramine, but not H2O2, significantly inhibited DNA methylation. Both oxidants inhibited DNA methyltransferase 1 activity, but only chloramine depleted SAM, suggesting that removal of substrate was the most effective means of inhibiting DNA methylation. These results indicate that immune cell–derived oxidants generated during inflammation have the potential to affect the epigenome of neighboring cells.