ID | 67720 |
FullText URL | |
Author |
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
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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.
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Keywords | DNA methylation
DNA methyltransferase
chemical modification
chemokine
cell proliferation
toxicology
exposome
environmental electrophiles
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Published Date | 2024-10-29
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Publication Title |
International Journal of Molecular Sciences
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Volume | volume25
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Issue | issue21
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Publisher | MDPI
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Start Page | 11592
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ISSN | 1661-6596
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Content Type |
Journal Article
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language |
English
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OAI-PMH Set |
岡山大学
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Copyright Holders | © 2024 by the authors.
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File Version | publisher
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PubMed ID | |
DOI | |
Web of Science KeyUT | |
Related Url | isVersionOf https://doi.org/10.3390/ijms252111592
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License | https://creativecommons.org/licenses/by/4.0/
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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
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Funder Name |
Ministry of Education, Culture, Sports, Science and Technology
Smoking Research Foundation
Japan Science and Technology Agency
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助成番号 | 22K19380
24H00678
24K09795
JPMJSP2126
JPMJFS2128
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