Lysine-specific demethylase 4A, Lysine-specific demethylase 4B, Lysine-specific demethylase 4C, Lysine-specific demethylase 4D (KDM4A (JMJD2A), KDM4B (JMJD2B), KDM4C (JMJD2C), KDM4D (JMJD2D))

Lysine-specific demethylase 4A–D (KDM4A–D) are a family of JmjC domain-containing enzymes that catalyze the removal of di- and tri-methyl marks from lysine residues on histone H3, specifically at lysines 9 (H3K9) and 36 (H3K36). These demethylases require Fe(II) and alpha-ketoglutarate as cofactors. The KDM4 family plays a central role in epigenetic regulation of chromatin, transcription, DNA replication timing, DNA damage response, and cell cycle control. Overexpression or dysregulation of KDM4A–D, particularly KDM4A, is implicated in various cancers and can lead to altered gene expression, enhanced proliferation, and chromosomal instability. These enzymes are considered promising therapeutic targets, and several small-molecule inhibitors are under development, particularly for oncology indications.

Other names

JMJD2AJHDM3ATDRD14BKIAA0677 (for KDM4A)JMJD2BJMJD2CJMJD2D (for B–D members)Histone lysine demethylase subfamily 4

Competitive inhibition of the alpha-ketoglutarate cofactor binding site in the JmjC domain; Inhibition of histone demethylase activity, leading to sustained histone methylation and gene repression/activation