Kdm5b, also known as Lysine-Specific Demethylase 5B, PLU1, or JARID1B, is a histone demethylase that erases the methyl group from H3K4me2/3, performing wide regulatory effects on chromatin structure and repressing gene transcriptional function. It is involved in multiple pathways related to cell differentiation, development, and cancer. Kdm5b has been found to be crucial in embryonic stem cell differentiation and the regulation of the H3K4-methylome during early mouse embryonic pre-implantation stage development [3,4].

In mouse melanoma models, depletion of Kdm5b induces robust adaptive immune responses and enhances responses to immune checkpoint blockade. Kdm5b recruits the H3K9 methyltransferase SETDB1 to repress endogenous retroelements in a demethylase-independent manner. Derepression of these retroelements activates cytosolic RNA-sensing and DNA-sensing pathways and the subsequent type-I interferon response, leading to tumour rejection and induction of immune memory, revealing its role in immune evasion in melanoma [1]. In nasopharyngeal carcinoma, specific inhibition of Kdm5B impairs tumour progression and reverses cisplatin resistance both in vitro and in vivo. Kdm5B also promotes tumorigenesis of Ewing sarcoma, and its knockdown and inhibition suppress EwS cell proliferation and induce cell cycle arrest [2,6]. In glioblastoma, KDM5B predicts temozolomide-resistant subclones, and its knockdown increases sensitivity to temozolomide [5].

In conclusion, Kdm5b is a key regulator in chromatin-related processes with significant impacts on development and multiple cancer types. The use of gene knockout or conditional knockout mouse models, along with in vitro functional studies, has been instrumental in revealing its role in immune evasion, drug resistance, and tumorigenesis, providing potential targets for cancer therapies.