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Okuda, Kosaku; Nakahara, Kengo; Ito, Akihiro; Iijima, Yuta; Nomura, Ryosuke; Kumar, Ashutosh; Fujikawa, Kana; Adachi, Kazuya; Shimada, Yuki; Fujio, Satoshi; Yamamoto, Reina; Takasugi, Nobumasa; Onuma, Kunishige; Osaki, Mitsuhiko; Okada, Futoshi; Ukegawa, Taichi; Takeuchi, Yasuo; Yasui, Norihisa; Yamashita, Atsuko; Marusawa, Hiroyuki; Matsushita, Yosuke; Katagiri, Toyomasa; Shibata, Takahiro; Uchida, Koji; [...]

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

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  • Medientyp: E-Artikel
  • Titel: Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis
  • Beteiligte: Okuda, Kosaku; Nakahara, Kengo; Ito, Akihiro; Iijima, Yuta; Nomura, Ryosuke; Kumar, Ashutosh; Fujikawa, Kana; Adachi, Kazuya; Shimada, Yuki; Fujio, Satoshi; Yamamoto, Reina; Takasugi, Nobumasa; Onuma, Kunishige; Osaki, Mitsuhiko; Okada, Futoshi; Ukegawa, Taichi; Takeuchi, Yasuo; Yasui, Norihisa; Yamashita, Atsuko; Marusawa, Hiroyuki; Matsushita, Yosuke; Katagiri, Toyomasa; Shibata, Takahiro; Uchida, Koji; [...]
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-023-36232-6
  • ISSN: 2041-1723
  • Schlagwörter: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with <jats:italic>S</jats:italic>-adenosyl-<jats:sc>l</jats:sc>-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 (<jats:italic>Ccnd2</jats:italic>), 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 <jats:italic>Ccnd2</jats:italic> expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit <jats:italic>S</jats:italic>-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits <jats:italic>S</jats:italic>-nitrosylation of DNMT3B at low concentrations (IC<jats:sub>50</jats:sub> ≤ 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 <jats:italic>S</jats:italic>-nitrosylation of DNMT3B.</jats:p>
  • Zugangsstatus: Freier Zugang