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

Author

Listed:
  • Kosaku Okuda

    (Okayama University)

  • Kengo Nakahara

    (Okayama University)

  • Akihiro Ito

    (Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science
    Tokyo University of Pharmacy and Life Sciences)

  • 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
    Tottori University)

  • Futoshi Okada

    (Tottori University
    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
    University of California, San Diego, School of Medicine)

  • Takashi Uehara

    (Okayama University)

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.

Suggested Citation

  • Kosaku Okuda & Kengo Nakahara & Akihiro Ito & Yuta Iijima & Ryosuke Nomura & Ashutosh Kumar & Kana Fujikawa & Kazuya Adachi & Yuki Shimada & Satoshi Fujio & Reina Yamamoto & Nobumasa Takasugi & Kunish, 2023. "Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36232-6
    DOI: 10.1038/s41467-023-36232-6
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    References listed on IDEAS

    as
    1. Takashi Uehara & Tomohiro Nakamura & Dongdong Yao & Zhong-Qing Shi & Zezong Gu & Yuliang Ma & Eliezer Masliah & Yasuyuki Nomura & Stuart A. Lipton, 2006. "S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration," Nature, Nature, vol. 441(7092), pages 513-517, May.
    2. Alexi Nott & P. Marc Watson & James D. Robinson & Luca Crepaldi & Antonella Riccio, 2008. "S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons," Nature, Nature, vol. 455(7211), pages 411-415, September.
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