The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia.
The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia.
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DOI：
10.1371/journal.pone.0131716
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chiang GG
中科院分区：
文献类型：
--
作者：
Pappano WN;Guo J;He Y;Ferguson D;Jagadeeswaran S;Osterling DJ;Gao W;Spence JK;Pliushchev M;Sweis RF;Buchanan FG;Michaelides MR;Shoemaker AR;Tse C;Chiang GG
组蛋白甲基转移酶是一种表观遗传调节剂，可以修饰组蛋白上的关键赖氨酸和精氨酸残基，被认为在癌症的发生和维持中发挥着重要作用。这些表观遗传修饰可能是可逆的，因此，这类酶作为小分子抑制剂的潜在治疗靶点引起了极大的兴趣。先前的研究表明，组蛋白赖氨酸甲基转移酶G9a(EHMT2)在多种癌症类型中通过多种机制维持恶性表型。为了进一步阐明G9a在癌症中的酶作用，我们在这里描述了一种新的多肽竞争性组蛋白甲基转移酶抑制剂A-366的生物学活性，它选择性地抑制G9a和密切相关的GLP(EHMT1)，但不抑制其他组蛋白甲基转移酶。与其他已知的G9a/GLP小分子抑制剂相比，A-366对肿瘤细胞系生长的细胞毒作用明显较小，尽管对H3K9me2甲基化的细胞活性相当。此外，A-366的选择性有助于发现G9a/GLP在白血病维持中的潜在重要作用。不同白血病细胞株体外作用后，细胞分化和形态发生明显变化。此外，用A-366处理侧翼异种移植白血病模型后，体内的生长抑制与观察到的H3K9me2减少的情况一致。综上所述，A-366是一种新型的、高选择性的G9a/GLP抑制剂，它使人们能够发现G9a/GLP酶活性在白血病细胞的生长和分化状态中所起的作用。
Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types. To further elucidate the enzymatic role of G9a in cancer, we describe herein the biological activities of a novel peptide-competitive histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1), but not other histone methyltransferases. A-366 has significantly less cytotoxic effects on the growth of tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite equivalent cellular activity on methylation of H3K9me2. Additionally, the selectivity profile of A-366 has aided in the discovery of a potentially important role for G9a/GLP in maintenance of leukemia. Treatment of various leukemia cell lines in vitro resulted in marked differentiation and morphological changes of these tumor cell lines. Furthermore, treatment of a flank xenograft leukemia model with A-366 resulted in growth inhibition in vivo consistent with the profile of H3K9me2 reduction observed. In summary, A-366 is a novel and highly selective inhibitor of G9a/GLP that has enabled the discovery of a role for G9a/GLP enzymatic activity in the growth and differentiation status of leukemia cells.
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影响因子：
3.7
作者：
Kondo Y;Shen L;Ahmed S;Boumber Y;Sekido Y;Haddad BR;Issa JP
通讯作者：
Issa JP
影响因子：
4.2
作者：
Kondo, Yutaka;Shen, Lanlan;Sekido, Yoshitaka
通讯作者：
Sekido, Yoshitaka
影响因子：
4.2
作者：
Sweis, Ramzi F.;Pliushchev, Marina;Pappano, William N.
通讯作者：
Pappano, William N.
影响因子：
16
作者：
Kubicek, Stefan;O'Sullivan, Roderick J.;Jenuwein, Thomas
通讯作者：
Jenuwein, Thomas
影响因子：
10.5
作者：
Tachibana, M;Ueda, J;Shinkai, Y
通讯作者：
Shinkai, Y