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ID 118929
Author
Okuda, Kosaku Okayama University
Nakahara, Kengo Okayama University
Ito, Akihiro RIKEN|Tokyo University
Iijima, Yuta Okayama University
Nomura, Ryosuke Okayama University
Kumar, Ashutosh RIKEN
Fujikawa, Kana Okayama University
Adachi, Kazuya Okayama University
Shimada, Yuki Okayama University
Fujio, Satoshi Okayama University
Yamamoto, Reina Okayama University
Takasugi, Nobumasa Okayama University
Onuma, Kunishige Tottori University
Osaki, Mitsuhiko Tottori University
Okada, Futoshi Tottori University
Ukegawa, Taichi Okayama University
Takeuchi, Yasuo Okayama University
Yasui, Norihisa Okayama University
Yamashita, Atsuko Okayama University
Marusawa, Hiroyuki Kyoto University
Shibata, Takahiro Nagoya University
Uchida, Koji The University of Tokyo
Niu, Sheng-Yong Broad Institute of MIT and Harvard
Lang, Nhi B. The Scripps Research Institute
Nakamura, Tomohiro The Scripps Research Institute
Zhang, Kam Y. J. RIKEN
Lipton, Stuart A. The Scripps Research Institute|University of California, San Diego
Uehara, Takashi Okayama University
Content Type
Journal Article
Description
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 ≤ 100 nM). 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.
Journal Title
Nature Communications
ISSN
20411723
NCID
AA12645905
Publisher
Springer Nature
Volume
14
Start Page
621
Published Date
2023-02-04
Rights
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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language
eng
TextVersion
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departments
Institute of Advanced Medical Sciences