Department of Cell Biology and Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Cancer Res. 2013 May 15;73(10):2936-42. doi: 10.1158/0008-5472.CAN-12-4300. Epub 2013 May 3.
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 under way to develop KDM4 inhibitors, which could complement the existing arsenal of epigenetic drugs that are currently limited to DNA methyltransferases and histone deacetylases.
赖氨酸甲基化是最主要的组蛋白翻译后修饰之一，可调节染色质结构。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失调或相反的去甲基酶的结果。KDM4/JMJD2 蛋白是针对赖氨酸 9 和 36 的组蛋白 H3 和赖氨酸 26 的组蛋白 H1.4 的去甲基酶。该蛋白家族由三个~130kDa 的蛋白（KDM4A-C）和 KDM4D/JMJD2D 组成，其大小为一半，缺乏双 PHD 和 Tudor 结构域，这些结构域是表观基因组的读取器，存在于其他 KDM4 蛋白中，并且具有不同的底物特异性。各种研究表明，KDM4A/JMJD2A、KDM4B/JMJD2B 和/或 KDM4C/JMJD2C 在乳腺癌、结直肠癌、肺癌、前列腺癌和其他肿瘤中过度表达，并且是有效癌细胞生长所必需的。部分原因可能是它们能够调节雄激素和雌激素受体等转录因子。因此，KDM4 蛋白本身就是潜在的新型药物靶点。因此，正在进行多种尝试来开发 KDM4 抑制剂，这可以补充目前仅限于 DNA 甲基转移酶和组蛋白去乙酰化酶的现有表观遗传药物库。
