EpiTherapeutics ApS, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Epigenomics. 2014 Jun;6(3):277-86. doi: 10.2217/epi.14.14.
There is growing evidence for a causal role of the KDM5 family of histone demethylases in human cancer. In particular, KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) contribute to cancer cell proliferation, reduce the expression of tumor suppressor genes, promote the development of drug tolerance and maintain tumor-initiating cells. KDM5 enzymes remove tri- and di-methylations of lysine 4 of histone H3 - modifications that occur at the start site of transcription in actively transcribed genes. However, the importance of the histone demethylase activity of KDM5 proteins for cancer cells has not been resolved so far. The currently available approaches suppress or remove the targeted proteins and thereby affect their putative functions as structural components and recruitment factors for other chromatin-associated proteins. Therefore, the development of specific enzymatic inhibitors for KDM5 will promote our understanding of the biological role of their catalytic activity and yield potential novel anticancer therapeutics.
越来越多的证据表明，组蛋白去甲基酶 KDM5 家族在人类癌症中起因果作用。特别是 KDM5A（JARID1A/RBP2）和 KDM5B（JARID1B/PLU1）促进癌细胞增殖，降低肿瘤抑制基因的表达，促进药物耐受的发展，并维持肿瘤起始细胞。KDM5 酶去除组蛋白 H3 赖氨酸 4 的三甲基和二甲基化修饰——这种修饰发生在转录起始位点，在活跃转录的基因中。然而，到目前为止，KDM5 蛋白的组蛋白去甲基酶活性对癌细胞的重要性尚未得到解决。目前可用的方法是抑制或去除靶向蛋白，从而影响它们作为其他染色质相关蛋白的结构成分和募集因子的潜在功能。因此，开发针对 KDM5 的特异性酶抑制剂将促进我们对其催化活性的生物学作用的理解，并产生潜在的新型抗癌治疗方法。
