Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis

Kosaku Okuda, Kengo Nakahara, Akihiro Ito, Yuta Iijima, Ryosuke Nomura, Ashutosh Kumar, Kana Fujikawa, Kazuya Adachi, Yuki Shimada, Satoshi Fujio, Reina Yamamoto, Nobumasa Takasugi, Kunishige Onuma, Mitsuhiko Osaki, Futoshi Okada, Taichi Ukegawa, Yasuo Takeuchi, Norihisa Yasui, Atsuko Yamashita, Hiroyuki Marusawa, Yosuke Matsushita, Toyomasa Katagiri, Takahiro Shibata, Koji Uchida, Sheng-Yong Niu, Nhi B. Lang, Tomohiro Nakamura, Kam Y. J. Zhang, Stuart A. Lipton () and Takashi Uehara ()
Additional contact information
Kosaku Okuda: Okayama University
Kengo Nakahara: Okayama University
Akihiro Ito: Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science
Yuta Iijima: Okayama University
Ryosuke Nomura: Okayama University
Ashutosh Kumar: Center for Biosystems Dynamics Research, RIKEN
Kana Fujikawa: Okayama University
Kazuya Adachi: Okayama University
Yuki Shimada: Okayama University
Satoshi Fujio: Okayama University
Reina Yamamoto: Okayama University
Nobumasa Takasugi: Okayama University
Kunishige Onuma: Tottori University
Mitsuhiko Osaki: Tottori University
Futoshi Okada: Tottori University
Taichi Ukegawa: Okayama University
Yasuo Takeuchi: Okayama University
Norihisa Yasui: Okayama University
Atsuko Yamashita: Okayama University
Hiroyuki Marusawa: Kyoto University
Yosuke Matsushita: Tokushima University, Tokushima
Toyomasa Katagiri: Tokushima University, Tokushima
Takahiro Shibata: Nagoya University
Koji Uchida: The University of Tokyo
Sheng-Yong Niu: Broad Institute of MIT and Harvard
Nhi B. Lang: The Scripps Research Institute
Tomohiro Nakamura: The Scripps Research Institute
Kam Y. J. Zhang: Center for Biosystems Dynamics Research, RIKEN
Stuart A. Lipton: The Scripps Research Institute
Takashi Uehara: Okayama University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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 ≤ 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.

Date: 2023
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DOI: 10.1038/s41467-023-36232-6

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