Lysine-specific demethylase 5 family (KDM5)

The KDM5 family of histone lysine demethylases, comprising KDM5A, KDM5B, KDM5C, and KDM5D, plays a critical role in epigenetic regulation by specifically removing methyl groups from tri- and di-methylated lysine 4 of histone H3 (H3K4me3/me2) [PMID: 28211445]. These enzymes are characterized by a catalytic Jumonji C (JmjC) domain and are essential for controlling gene expression patterns during development and cellular differentiation [PMID: 24569484]. In oncology, KDM5 members are frequently overexpressed and act as oncogenes; for instance, KDM5A is associated with the emergence of drug-tolerant persister cells that contribute to chemotherapy resistance, while KDM5B is a well-known driver in breast and prostate cancers [PMID: 21326095]. Therapeutic strategies targeting the KDM5 family primarily involve small-molecule inhibitors that compete with the co-factor alpha-ketoglutarate, thereby restoring H3K4 methylation levels and potentially reversing malignant phenotypes [PMID: 27043296]. Beyond cancer, mutations in KDM5C are a recognized cause of X-linked intellectual disability, highlighting the family's importance in neurological function [PMID: 17417636].

Other names

JARID1 familyJumonji/ARID domain-containing protein 1 familyH3K4 demethylasesRetinoblastoma-binding protein 2 family

Competitive inhibition of the alpha-ketoglutarate (2-OG) binding site within the JmjC catalytic domain, preventing the demethylation of H3K4me3/me2 and thereby modulating gene expression [PMID: 27043296].