Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis.
Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis.
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DOI：
10.1038/s41467-023-36232-6
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发表时间：
2023-02-04
影响因子：
16.6
通讯作者：
Uehara, Takashi
中科院分区：
文献类型：
--
作者：
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;Niu, Sheng-Yong;Lang, Nhi B.;Nakamura, Tomohiro;Zhang, Kam Y. J.;Lipton, Stuart A.;Uehara, Takashi
DNA 甲基转移酶 (DNMT) 通过 S-腺苷-L-甲硫氨酸催化胞嘧啶 C5 位点的甲基化。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。这些基因包括细胞周期蛋白 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。该先导化合物，命名为 DBIC，在低浓度 (IC50≤≤100nM) 下抑制 DNMT3B 的 S-亚硝基化。 DBIC 治疗可在体外预防一氧化氮 (NO) 诱导的人结肠腺瘤向腺癌的转化。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。在这里，作者证明了 DNMT3B 介导的 DNA 从头甲基化受到一氧化氮 (NO) 的调节。他们还分离出一种独特的调节剂 (DBIC)，该调节剂可抑制 DNMT3B 的 S-亚硝基化，从而减轻体内细胞增殖和致瘤转化。
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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影响因子：
11.2
作者：
Cole AM;Myant K;Reed KR;Ridgway RA;Athineos D;Van den Brink GR;Muncan V;Clevers H;Clarke AR;Sicinski P;Sansom OJ
通讯作者：
Sansom OJ
影响因子：
2.9
作者：
Kaufmann, Kristian W.;Lemmon, Gordon H.;DeLuca, Samuel L.;Sheehan, Jonathan H.;Meiler, Jens
通讯作者：
Meiler, Jens
DOI：
10.1016/j.ymeth.2014.07.007
发表时间：
2015-01
期刊：
Methods (San Diego, Calif.)
影响因子：
--
作者：
Kumar A;Zhang KY
通讯作者：
Zhang KY
影响因子：
5.6
作者：
Halgren, Thomas A.
通讯作者：
Halgren, Thomas A.
影响因子：
3.7
作者：
Gokul G;Gautami B;Malathi S;Sowjanya AP;Poli UR;Jain M;Ramakrishna G;Khosla S
通讯作者：
Khosla S