期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2200022119
关键词
nitric oxide; NOS2; DNA methylation; retrotransposon; S-nitrosation
资金
- British Heart Foundation [IG/16/2/32273, PG/19/33/34385]
- Barts Charity Cardiovascular Programme [G00913]
- Medical Research Council
- National Institute of Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust and King's College London
- Centre of Excellence in Medical Engineering - Wellcome Trust
- Engineering and Physical Sciences Research Council [WT 203148/Z/16/Z]
- British Heart Foundation Centre of Research Excellence grant [RE/18/2/34213]
- Wellcome Trust [202767/Z/16/Z]
- Medical Research Council [G1100238/1]
- Wellcome Trust [202767/Z/16/Z] Funding Source: Wellcome Trust
Inducible nitric oxide synthase (NOS2) and nitric oxide (NO) signaling lead to DNA hypomethylation and genomic instability through degradation of DNMT1 protein and retrotransposon activation. NOS2 expression levels are correlated with decreased DNA methylation and malignant cellular transformation in breast cancer patients.
Inducible nitric oxide synthase (NOS2) produces high local concentrations of nitric oxide (NO), and its expression is associated with inflammation, cellular stress signals, and cellular transformation. Additionally, NOS2 expression results in aggressive cancer cell phenotypes and is correlated with poor outcomes in patients with breast cancer. DNA hypomethylation, especially of noncoding repeat elements, is an early event in carcinogenesis and is a common feature of cancer cells. In addition to altered gene expression, DNA hypomethylation results in genomic instability via retrotransposon activation. Here, we show that NOS2 expression and associated NO signaling results in substantial DNA hypomethylation in human cell lines by inducing the degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) protein. Similarly, NOS2 expression levels were correlated with decreased DNA methylation in human breast tumors. NOS2 expression and NO signaling also resulted in long interspersed noncoding element 1 (LINE-1) retrotransposon hypomethylation, expression, and DNA damage. DNMT1 degradation was mediated by an NO/p38-MAPK/lysine acetyltransferase 5-dependent mechanism. Furthermore, we show that this mechanism is required for NO-mediated epithelial transformation. Therefore, we conclude that NOS2 and NO signaling results in DNA damage and malignant cellular transformation via an epigenetic mechanism.
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