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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA120.013092