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 Fe2+- 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.
Keywords: Cancer; Drug resistance; Histone demethylation; JmjC domain; KDM6A; Targeting therapy.
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