KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells.
KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells.
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DOI：
10.1158/0008-5472.can-12-4300
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发表时间：
2013-05-15
期刊：
影响因子：
11.2
通讯作者：
Janknecht R
中科院分区：
文献类型：
--
作者：
Berry WL;Janknecht R
赖氨酸甲基化是调节染色质结构的最重要的组蛋白翻译后修饰之一。在癌症形成过程中观察到组蛋白赖氨酸甲基化状态的变化，这被认为是组蛋白赖氨酸甲基转移酶或相反的脱甲基酶调节异常的结果。KDM 4/JMJD 2蛋白是靶向赖氨酸9和36上的组蛋白H3和赖氨酸26上的组蛋白H1.4的脱甲基酶。该蛋白质家族由三个~130 kDa蛋白质（KDM 4A-C）和KDM 4D/JMJD 2D组成，其大小为一半，缺乏作为表观基因组阅读器并存在于其他KDM 4蛋白质中的双PHD和Tudor结构域，并且具有不同的底物特异性。各种研究表明，KDM 4A/JMJD 2A、KDM 4 B/JMJD 2B和/或KDM 4C/JMJD 2C在乳腺、结肠直肠、肺、前列腺和其他肿瘤中过表达，并且是有效癌细胞生长所需的。在某种程度上，这可能是由于它们能够调节转录因子，如雄激素和雌激素受体。因此，KDM 4蛋白本身是新的潜在药物靶点。因此，正在进行多种尝试来开发KDM 4抑制剂，其可以补充目前仅限于DNA甲基转移酶和组蛋白脱乙酰酶的表观遗传药物的现有武库。
Lysine methylation is one of the most prominent histone posttranslational modifications that regulate chromatin structure. Changes in histone lysine methylation status have been observed during cancer formation, which is thought to be a consequence of the dysregulation of histone lysine methyltransferases or the opposing demethylases. KDM4/JMJD2 proteins are demethylases that target histone H3 on lysines 9 and 36 and histone H1.4 on lysine 26. This protein family consists of three ~130 kDa proteins (KDM4A–C) and KDM4D/JMJD2D, which is half the size, lacks the double PHD and Tudor domains that are epigenome readers and present in the other KDM4 proteins, and has a different substrate specificity. Various studies have shown that KDM4A/JMJD2A, KDM4B/JMJD2B and/or KDM4C/JMJD2C are overexpressed in breast, colorectal, lung, prostate and other tumors and are required for efficient cancer cell growth. In part, this may be due to their ability to modulate transcription factors such as the androgen and estrogen receptor. Thus, KDM4 proteins present themselves as novel potential drug targets. Accordingly, multiple attempts are underway to develop KDM4 inhibitors, which could complement the existing arsenal of epigenetic drugs that are currently limited to DNA methyltransferases and histone deacetylases.