Lysine-specific demethylase 6 family (KDM6)

The Lysine-specific demethylase 6 (KDM6) family consists of JmjC domain-containing enzymes, primarily KDM6A (UTX), KDM6B (JMJD3), and KDM6C (UTY), that specifically catalyze the removal of repressive methyl marks from lysine 27 of histone H3 (H3K27me2/3). By removing these marks, KDM6 proteins facilitate chromatin opening and the activation of genes essential for embryonic development, cell lineage commitment, and the regulation of inflammatory responses (1.2.1, 1.3.3). These enzymes are frequently dysregulated in various pathologies, including hematologic malignancies and solid tumors, where they can act as either oncogenes or tumor suppressors depending on the specific cellular and genetic context (1.2.2, 1.4.2). In addition to cancer, the KDM6 family plays a critical role in mediating pro-inflammatory gene expression in autoimmune conditions such as rheumatoid arthritis and multiple sclerosis (1.2.3). Therapeutic strategies targeting this family involve small-molecule inhibitors like GSK-J4, which aim to restore repressive H3K27me3 marks on oncogenic or inflammatory promoters (1.1.1, 1.1.2). However, the clinical application of these inhibitors faces challenges regarding target selectivity and the potential for broad, off-target epigenetic toxicity (1.2.1, 1.2.2).

Other names

KDM6 subfamilyH3K27 demethylase familyJmjC domain-containing histone demethylase 6 familyUTX/JMJD3 family

Inhibition of the JmjC catalytic domain to prevent the demethylation of di- and tri-methylated lysine 27 on histone H3 (H3K27me2/3), thereby maintaining gene repression.