State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo 315211, Zhejiang, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China; Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China.
School of Life Science and Engineering, Henan University of Urban Construction, Pingdingshan 467044, Henan, China.
Bioorg Chem. 2023 Apr;133:106409. doi: 10.1016/j.bioorg.2023.106409. Epub 2023 Feb 4.
Histone demethylation is a key post-translational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Lysine specific demethylase 6A (KDM6A, also known as UTX) is an Fe- and α-ketoglutarate- dependent oxidase which belongs to KDM6 Jumonji histone demethylase subfamily, and it can remove mono-, di- and tri-methyl groups from methylated lysine 27 of histone H3 (H3K27me1/2/3). Mounting studies indicate that KDM6A is responsible for driving multiple human diseases, particularly cancers and pharmacological inhibition of KDM6A is an effective strategy to treat varieties of KDM6A-amplified cancers in cellulo and in vivo. Although there are several reviews on the roles of KDM6 subfamily in cancer development and therapy, all of them only simply introduce the roles of KDM6A in cancer without systematically summarizing the specific mechanisms of KDM6A in tumorigenesis, which greatly limits the advances on the understanding of roles KDM6A in varieties of cancers, discovering targeting selective KDM6A inhibitors, and exploring the adaptive profiles of KDM6A antagonists. Herein, we present the structure and functions of KDM6A, simply outline the functions of KDM6A in homeostasis and non-cancer diseases, summarize the role of KDM6A and its distinct target genes/ligand proteins in development of varieties of cancers, systematically classify KDM6A inhibitors, sum up the difficulties encountered in the research of KDM6A and the discovery of related drugs, and provide the corresponding solutions, which will contribute to understanding the roles of KDM6A in carcinogenesis and advancing the progression of KDM6A as a drug target in cancer therapy.
组蛋白去甲基化是染色质的一种关键的翻译后修饰，其失调会影响广泛的核活动，包括基因组完整性的维持、转录调控和表观遗传遗传。赖氨酸特异性去甲基酶 6A（KDM6A，也称为 UTX）是一种铁和α-酮戊二酸依赖性氧化酶，属于 KDM6 Jumonji 组蛋白去甲基酶亚家族，它可以去除组蛋白 H3 赖氨酸 27 上的单、二和三甲基化（H3K27me1/2/3）。越来越多的研究表明，KDM6A 负责驱动多种人类疾病，特别是癌症，而抑制 KDM6A 的药理学作用是在细胞内和体内治疗多种 KDM6A 扩增癌症的有效策略。尽管有几篇关于 KDM6 亚家族在癌症发展和治疗中的作用的综述，但它们都只是简单地介绍了 KDM6A 在癌症中的作用，而没有系统地总结 KDM6A 在肿瘤发生中的具体机制，这极大地限制了对 KDM6A 在各种癌症中的作用的理解、发现针对选择性 KDM6A 的抑制剂，以及探索 KDM6A 拮抗剂的适应性特征的进展。在这里，我们介绍了 KDM6A 的结构和功能，简单概述了 KDM6A 在体内平衡和非癌症疾病中的功能，总结了 KDM6A 在多种癌症发展中的作用及其独特的靶基因/配体蛋白，系统地分类了 KDM6A 抑制剂，总结了 KDM6A 研究和相关药物发现中遇到的困难，并提供了相应的解决方案，这将有助于理解 KDM6A 在致癌作用中的作用，并推进 KDM6A 作为癌症治疗药物靶点的进展。
