NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression

TY - JOUR

T1 - NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression

AU - Switzer, Christopher H.

AU - Cho, Hyun Ju

AU - Eykyn, Thomas R.

AU - Lavender, Paul

AU - Eaton, Philip

N1 - Funding Information: ACKNOWLEDGMENTS. C.H.S. is supported by British Heart Foundation Project Grant PG/19/33/34385. P.E. is supported by The Barts Charity Cardiovascular Programme Award G00913 and by program grants from the British Heart Foundation and the Medical Research Council. T.R.E. acknowledges support from the 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; the Centre of Excellence in Medical Engineering, funded by the Wellcome Trust and Engineering and Physical Sciences Research Council grant (WT 203148/Z/16/Z); and the British Heart Foundation Centre of Research Excellence grant (RE/18/2/34213). The Centre for Biomolecular Spectroscopy is funded by grants from the Wellcome Trust (202767/Z/16/Z) and British Heart Foundation (IG/16/2/32273). P.L. was supported by Medical Research Council Grant G1100238/1. We thank the BRC Genomics Platform at the NIHR Biomedical Research Centre at Guy’s and St. Thomas’ Hospitals, London. We thank Miguel Branco (Blizzard Institute, Queen Mary University of London) for LINE-1 primers and plasmids and helpful discussions regarding the manuscript. We thank A. Riggs, T. Dawson, R. Davis, and W. Sellers for providing plasmids. We also thank Stefan Ambs (National Cancer Institute, NIH) for providing tumor NOS2 expression annotations and David Wink and Robert Cheng (National Cancer Institute, NIH) for sharing the NOS2 TRANSFAC data set. Publisher Copyright: Copyright © 2022 the Author(s).

PY - 2022/5/24

Y1 - 2022/5/24

N2 - 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.

AB - 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.

KW - DNA methylation

KW - nitric oxide

KW - NOS2

KW - retrotransposon

KW - S-nitrosation

UR - http://www.scopus.com/inward/record.url?scp=85130766519&partnerID=8YFLogxK

U2 - 10.1073/pnas.2200022119

DO - 10.1073/pnas.2200022119

M3 - Article

C2 - 35584114

AN - SCOPUS:85130766519

SN - 0027-8424

VL - 119

SP - e2200022119

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 21

M1 - e2200022119

ER -