2023年2月6日 / 最終更新日 : 2023年2月6日 ad_y ニュース

2023年 新着論文 6　ゲノム制御学分野から論文が発表されました

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

Nat Commun. 2023 Feb 4;14(1):621. doi: 10.1038/s41467-023-36232-6.

Authors

Kosaku Okuda #  1 , Kengo Nakahara #  1 , Akihiro Ito #  2   3 , Yuta Iijima  1 , Ryosuke Nomura  1 , Ashutosh Kumar  4 , Kana Fujikawa  1 , Kazuya Adachi  1 , Yuki Shimada  1 , Satoshi Fujio  1 , Reina Yamamoto  1 , Nobumasa Takasugi  1 , Kunishige Onuma  5 , Mitsuhiko Osaki  5   6 , Futoshi Okada  5   6 , Taichi Ukegawa  7 , Yasuo Takeuchi  7 , Norihisa Yasui  8 , Atsuko Yamashita  8 , Hiroyuki Marusawa  9 , Yosuke Matsushita  10 , Toyomasa Katagiri  10 , Takahiro Shibata  11 , Koji Uchida  12 , Sheng-Yong Niu  13 , Nhi B Lang  14 , Tomohiro Nakamura  14 , Kam Y J Zhang  4 , Stuart A Lipton  15   16 , Takashi Uehara  17

Affiliations

  • 1 Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • 2 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
  • 3 Laboratory of Cell Signaling, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
  • 4 Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa, Japan.
  • 5 Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago, Japan.
  • 6 Chromosome Engineering Research Center, Tottori University, Yonago, Japan.
  • 7 Department of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • 8 Laboratory of Structural Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • 9 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 10 Division of Genome Medicine, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Tokushima, Japan.
  • 11 Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
  • 12 Laboratory of Food Chemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
  • 13 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 14 Neurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
  • 15 Neurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, La Jolla, CA, USA. slipton@scripps.edu.
  • 16 Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA. slipton@scripps.edu.
  • 17 Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan. uehara-t@okayama-u.ac.jp.
# Contributed equally.

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.

カテゴリー
ニュース