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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.
Here the authors demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by nitric oxide (NO). They also isolate a unique modulator (DBIC) that inhibits S-nitrosylation of DNMT3B, which mitigates cell proliferation and tumorigenic conversion in vivo.
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1 Okayama University, Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (GRID:grid.261356.5) (ISNI:0000 0001 1302 4472)
2 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan (GRID:grid.509461.f) (ISNI:0000 0004 1757 8255); Tokyo University of Pharmacy and Life Sciences, Laboratory of Cell Signaling, Hachioji, Japan (GRID:grid.410785.f) (ISNI:0000 0001 0659 6325)
3 Center for Biosystems Dynamics Research, RIKEN, Laboratory for Structural Bioinformatics, Yokohama, Japan (GRID:grid.7597.c) (ISNI:0000000094465255)
4 Tottori University, Division of Experimental Pathology, Faculty of Medicine, Yonago, Japan (GRID:grid.265107.7) (ISNI:0000 0001 0663 5064)
5 Tottori University, Division of Experimental Pathology, Faculty of Medicine, Yonago, Japan (GRID:grid.265107.7) (ISNI:0000 0001 0663 5064); Tottori University, Chromosome Engineering Research Center, Yonago, Japan (GRID:grid.265107.7) (ISNI:0000 0001 0663 5064)
6 Okayama University, Department of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (GRID:grid.261356.5) (ISNI:0000 0001 1302 4472)
7 Okayama University, Laboratory of Structural Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (GRID:grid.261356.5) (ISNI:0000 0001 1302 4472)
8 Kyoto University, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033)
9 Tokushima University, Tokushima, Division of Genome Medicine, Institute of Advanced Medical Sciences, Tokushima, Japan (GRID:grid.267335.6) (ISNI:0000 0001 1092 3579)
10 Nagoya University, Graduate School of Bioagricultural Sciences, Nagoya, Japan (GRID:grid.27476.30) (ISNI:0000 0001 0943 978X)
11 The University of Tokyo, Laboratory of Food Chemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X)
12 Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623)
13 The Scripps Research Institute, Neurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, La Jolla, USA (GRID:grid.214007.0) (ISNI:0000000122199231)
14 The Scripps Research Institute, Neurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, La Jolla, USA (GRID:grid.214007.0) (ISNI:0000000122199231); University of California, San Diego, School of Medicine, Department of Neurosciences, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)