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ID 67720
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Tsuchida, Tomoki Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Kubota, Sho Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Kamiuezono, Shizuki Department of Medicinal Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University
Takasugi, Nobumasa Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Ito, Akihiro School of Life Sciences, Tokyo University of Pharmacy and Life Sciences
Kumagai, Yoshito Graduate School of Pharmaceutical Sciences, Kyushu University
Uehara, Takashi Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID
Abstract
Ubiquitously distributed environmental electrophiles covalently modify DNA and proteins, potentially leading to adverse health effects. However, the impacts of specific electrophiles on target proteins and their physiological roles remain largely unknown. In the present study, we focused on DNA methylation, which regulates gene expression and physiological responses. A total of 45 environmental electrophiles were screened for inhibitory effects on the activity of DNA methyltransferase 3B (DNMT3B), a key enzyme in DNA methylation, and four compounds were identified. We focused on 1,2-naphthoquinone (1,2-NQ), an air pollutant whose toxicity has been reported previously. Interestingly, we found that 1,2-NQ modified multiple lysine and histidine residues in DNMT3B, one of which was near the active site in DNMT3B. It was found that 1,2-NQ altered gene expression and evoked inflammatory responses in lung adenocarcinoma cell lines. Furthermore, we found that 1,2-NQ upregulated CXCL8 expression through DNA demethylation of the distal enhancer and promoted cancer cell growth. Our study reveals novel mechanisms of epigenetic regulation by environmental electrophiles through the inhibition of DNMT3B activity and suggests their physiological impact.
Keywords
DNA methylation
DNA methyltransferase
chemical modification
chemokine
cell proliferation
toxicology
exposome
environmental electrophiles
Published Date
2024-10-29
Publication Title
International Journal of Molecular Sciences
Volume
volume25
Issue
issue21
Publisher
MDPI
Start Page
11592
ISSN
1661-6596
Content Type
Journal Article
language
English
OAI-PMH Set
岡山大学
Copyright Holders
© 2024 by the authors.
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publisher
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Web of Science KeyUT
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isVersionOf https://doi.org/10.3390/ijms252111592
License
https://creativecommons.org/licenses/by/4.0/
Citation
Tsuchida, T.; Kubota, S.; Kamiuezono, S.; Takasugi, N.; Ito, A.; Kumagai, Y.; Uehara, T. Epigenetic Regulation of CXC Chemokine Expression by Environmental Electrophiles Through DNA Methyltransferase Inhibition. Int. J. Mol. Sci. 2024, 25, 11592. https://doi.org/10.3390/ijms252111592
Funder Name
Ministry of Education, Culture, Sports, Science and Technology
Smoking Research Foundation
Japan Science and Technology Agency
助成番号
22K19380
24H00678
24K09795
JPMJSP2126
JPMJFS2128