<br>DNA甲基转移酶3B的S-亚硝基化在肿瘤发生的表观遗传调控中的关键作用,Nature Communications

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DNA甲基转移酶3B的S-亚硝基化在肿瘤发生的表观遗传调控中的关键作用
Nature Communications ( IF 14.7 ) Pub Date : 2023-02-04 , DOI: 10.1038/s41467-023-36232-6
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 _{14,

15} , Takashi Uehara ₁

Affiliation

Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
Laboratory of Cell Signaling, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa, Japan.
Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago, Japan.
Chromosome Engineering Research Center, Tottori University, Yonago, Japan.
Department of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Laboratory of Structural Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Division of Genome Medicine, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Tokushima, Japan.
Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
Laboratory of Food Chemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Neurodegeneration New Medicines Center, and Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA.

DNA 甲基转移酶 (DNMT) 催化胞嘧啶 C5 位点与S-腺苷-L-甲硫氨酸的甲基化。甲基化调节基因表达，发挥多种生理和病理生理作用。然而，调节 DNMT 酶活性的化学机制尚未完全阐明。在这里，我们发现 DNMT3B 中半胱氨酸残基的蛋白质 S-亚硝基化会减弱 DNMT3B 酶活性以及随之而来的基因表达的异常上调。这些基因包括 Cyclin D2 ( Ccnd2 )，它是某些肿瘤类型中肿瘤细胞增殖所必需的。在基于细胞和体内的癌症模型中，只有 DNMT3B 酶活性影响Ccnd2表达，而 DNMT1 或 DNMT3A 不受影响。通过基于结构的虚拟筛选，我们发现了特异性抑制S-亚硝基化而不直接影响 DNMT3B 酶活性的化合物。先导化合物（称为 DBIC）在低浓度 (IC ₅₀ ≤ 100 nM) 下抑制 DNMT3B 的S-亚硝基化。 DBIC 治疗可防止一氧化氮 (NO) 诱导的体外人结肠腺瘤转化为腺癌。此外，在由炎症诱导的 NO 生成引发的致癌小鼠模型中，使用 DBIC 进行体内治疗可显着减弱肿瘤的发展。我们的结果表明，DNMT3B 介导的从头 DNA 甲基化受 NO 调节，DBIC 通过阻止 DNMT3B 的异常S-亚硝基化来防止肿瘤形成。

"点击查看英文标题和摘要"

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

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.

更新日期：2023-02-04

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