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Okuda, Kosaku Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Nakahara, Kengo Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Ito, Akihiro Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science
Iijima, Yuta Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Nomura, Ryosuke Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Kumar, Ashutosh Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN
Fujikawa, Kana Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Adachi, Kazuya Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Shimada, Yuki Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Fujio, Satoshi Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Yamamoto, Reina Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Takasugi, Nobumasa Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Onuma, Kunishige Division of Experimental Pathology, Faculty of Medicine, Tottori University
Osaki, Mitsuhiko Division of Experimental Pathology, Faculty of Medicine, Tottori University
Okada, Futoshi Division of Experimental Pathology, Faculty of Medicine, Tottori University
Ukegawa, Taichi Department of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Takeuchi, Yasuo Department of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Kaken ID
Yasui, Norihisa Laboratory of Structural Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University ORCID Kaken ID publons researchmap
Yamashita, Atsuko Laboratory of Structural Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University ORCID Kaken ID publons researchmap
Marusawa, Hiroyuki Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University
Matsushita, Yosuke Division of Genome Medicine, Institute of Advanced Medical Sciences, Tokushima University
Katagiri, Toyomasa Division of Genome Medicine, Institute of Advanced Medical Sciences, Tokushima University
Shibata, Takahiro Graduate School of Bioagricultural Sciences, Nagoya University
Uchida, Koji Laboratory of Food Chemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
Niu, Sheng-Yong Broad Institute of MIT and Harvard
Lang, Nhi B. Neurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute
Nakamura, Tomohiro Neurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute
Zhang, Kam Y. J. Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN
Lipton, Stuart A. Neurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute
Uehara, Takashi Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University ORCID Kaken ID
Abstract
DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-l-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC50 <= 100nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B.
Note
The version of record of this article, first published in Nature Communications, is available online at Publisher’s website: http://dx.doi.org/10.1038/s41467-023-36232-6
Published Date
2023-02-04
Publication Title
Nature Communications
Volume
volume14
Issue
issue1
Publisher
Nature Portfolio
Start Page
621
ISSN
2041-1723
Content Type
Journal Article
language
English
OAI-PMH Set
岡山大学
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© The Author(s) 2023
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isVersionOf https://doi.org/10.1038/s41467-023-36232-6
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http://creativecommons.org/licenses/by/4.0/
Citation
Okuda, K., Nakahara, K., Ito, A. et al. Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis. Nat Commun 14, 621 (2023). https://doi.org/10.1038/s41467-023-36232-6