Nastaranpour Mahsa, Damara Aman, Grabbe Stephan, Shahneh Fatemeh
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
Biomed Pharmacother. 2025 Aug;189:118254. doi: 10.1016/j.biopha.2025.118254. Epub 2025 Jun 13.
Epigenetic dynamics, which influence gene expressions independent of DNA sequence alterations, play a pivotal role in regulating chromatin structure and transcription. Among these modifications, the dynamic methylation and demethylation of histone 3 lysine 27 (H3K27me2/3) by the Lysine Demethylase 6 (KDM6) subfamily are pivotal regulators of both physiological and pathological processes. In immune cells, KDM6A and KDM6B fine-tune the transcription of pro- and anti-inflammatory genes, influencing differentiation, polarization, and activation states in monocytes, macrophages, dendritic cells, T helper cells, and other key immune subsets. Dysregulated KDM6 activity underlies aberrant cytokine production, Th17 cell expansion, and imbalances in tissue repair responses, thus contributing to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Concurrently, KDM6A and KDM6B can act as either tumor suppressors or oncogenes in a context-dependent manner, mediating cellular proliferation, DNA damage repair pathways, and immune evasion in cancers ranging from hematologic malignancies to solid tumors of the bladder, breast, and brain. Recent efforts to exploit this duality include developing small-molecule inhibitors, notably GSK-J4, which block KDM6 demethylase activity and show promising therapeutic effects in models of chronic inflammation and cancer. Nonetheless, challenges such as incomplete target specificity, the interplay with other epigenetic mechanisms, and variations in tumor microenvironment emphasize the complexity of translating these findings into clinical practice. This review highlights the structural features, regulatory mechanisms, and disease associations of KDM6 demethylases, positioning them as compelling biomarkers and therapeutic targets at the intersection of autoimmunity and cancer.
表观遗传动力学独立于DNA序列改变影响基因表达，在调节染色质结构和转录中起关键作用。在这些修饰中，赖氨酸去甲基化酶6（KDM6）亚家族对组蛋白3赖氨酸27（H3K27me2/3）的动态甲基化和去甲基化是生理和病理过程的关键调节因子。在免疫细胞中，KDM6A和KDM6B微调促炎和抗炎基因的转录，影响单核细胞、巨噬细胞、树突状细胞、辅助性T细胞和其他关键免疫亚群的分化、极化和激活状态。KDM6活性失调是细胞因子产生异常、Th17细胞扩增和组织修复反应失衡的基础，从而导致类风湿性关节炎、系统性红斑狼疮和多发性硬化症等自身免疫性疾病。同时，KDM6A和KDM6B可以在依赖于背景的情况下充当肿瘤抑制因子或致癌基因，介导从血液系统恶性肿瘤到膀胱、乳腺和脑实体瘤等多种癌症中的细胞增殖、DNA损伤修复途径和免疫逃逸。最近利用这种双重性的努力包括开发小分子抑制剂，特别是GSK-J4，它阻断KDM6去甲基化酶活性，并在慢性炎症和癌症模型中显示出有前景的治疗效果。尽管如此，诸如不完全的靶点特异性、与其他表观遗传机制的相互作用以及肿瘤微环境的变化等挑战强调了将这些发现转化为临床实践的复杂性。本综述强调了KDM6去甲基化酶的结构特征、调节机制和疾病关联，将它们定位为自身免疫和癌症交叉点上引人注目的生物标志物和治疗靶点。
