Lysine-specific demethylase 5D (KDM5D)

Lysine-specific demethylase 5D (KDM5D) is a Y chromosome-encoded enzyme of the KDM5/JARID1 family, responsible for *demethylating di- and trimethylated lysine 4 on histone H3 (H3K4me2/3)*, a key epigenetic mark associated with active transcription[1]. KDM5D regulates gene expression, chromatin structure, and cell fate decisions by modifying histone methylation and interacting with other chromatin regulators including histone deacetylases[1]. While its primary role is in epigenetic regulation within the nucleus, KDM5D can also interact with non-histone proteins such as the kinase p38α, where it demethylates K165 and inactivates downstream signaling to suppress tumor progression[2]. KDM5D is implicated in cancer by influencing cell proliferation, migration, chemoresistance (notably to platinum agents), and may serve as both a tumor suppressor or oncogene depending on cellular context[2][3][4]. Due to its diverse roles and selective expression in male tissues, KDM5D is under investigation as a potential therapeutic target and as a biomarker in oncology, particularly for sex-specific differences in disease[2][3][4].

Other names

Lysine demethylase 5DJARID1DSMCYHYHYAKIAA0234Histocompatibility Y antigenHistone demethylase JARID1DJumonji/ARID domain-containing protein 1DProtein SmcY[histone H3]-trimethyl-L-lysine(4) demethylase 5Depididymis secretory sperm binding proteinJumonji, AT rich interactive domain 1D (RBP2-like)Selected mouse cDNA on Y, human homolog of

Inhibitors of KDM5D would block demethylase activity, increasing levels of H3K4 methylation, influencing gene expression. Disruption of KDM5D-mediated demethylation sensitizes cancer cells to DNA-damaging agents (e.g., cisplatin), possibly by preventing the emergence of drug-tolerant persister cells[3]. Modulation of non-histone protein methylation, such as demethylation of p38α at K165, affecting downstream signaling pathways[2].