KDM4A

Last update 08 May 2025

Basic Info

Synonyms

[histone H3]-trimethyl-L-lysine(36) demethylase 4A, [histone H3]-trimethyl-L-lysine(9) demethylase 4A, JHDM3A

+ [14]

Introduction

Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code (PubMed:26741168, PubMed:21768309). Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively. Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.

100 Clinical Results associated with KDM4A

100 Translational Medicine associated with KDM4A

0 Patents (Medical) associated with KDM4A

401

Literatures (Medical) associated with KDM4A

01 Sep 2025·Journal of Environmental Sciences

Carbon black induced pulmonary fibrosis through piR-713551/PIWIL4 targeting THBS2 signal pathway

Article

Author: Wang, Jingyuan ; Bao, Lei ; Pang, Yaxian ; Du, Zhe ; Niu, Yong ; Wu, Ruiting ; Wu, Mengqi ; Wang, Mengruo ; Yang, Peihao ; Zhang, Rong ; Shi, Beibei ; Liu, Qingping ; Niu, Yujie ; Chen, Jiawei

Carbon black (CB) is a vital constituent of airborne pollutants, comprising diesel exhaust and fine particulate matter (PM_2.5), as well as a prevalent manufacturing material. CB was known to cause pulmonary dysfunction and fibrosis. However, the detailed molecular mechanisms underlying fibrosis development are poorly understood. In this study, 18 C57BL/6 mice were randomized into two groups and exposed to CB and filtered air (FA) for 28 days, with 6 hr/day and 7 days per week exposure regimen, respectively. The human normal bronchial epithelial cell line (BEAS-2B) was subjected to CB treatment for 24 h in vitro, with CB concentrations in 0, 50, 100, and 200 µg/mL. Our study indicated that exposure to CB resulted in a reduction in lung function and the development of pulmonary fibrosis in mice. Furthermore, our results showed cytoskeleton rearrangement and epithelial-mesenchymal transition (EMT) phenotype in BEAS-2B cells were happened, after CB exposure. Subsequent studies revealed that elevated expression of THBS2 after CB primarily contributed to the development of pulmonary fibrosis. The research findings from both in vivo and in vitro studies provided evidence that piR-713551 was involved in CB exposure-induced EMT by targeting the THBS2 gene and activating the β-catenin pathway. Mechanically, piR-713551/PIWIL4 complex activated the THBS2 transcription by recruitment of histone demethyltransferase KDM4A to reduce H3K9me3 modification at the THBS2 gene promoter. Conclusively, our research showed that CB exposure could activate EMT and lead pulmonary fibrosis which was modulated by piR-713551/PIWIL4 targeting THBS2.

01 Apr 2025·Molecular Carcinogenesis

Glutamine, Serine and Glycine at Increasing Concentrations Regulate Cisplatin Sensitivity in Gastric Cancer by Posttranslational Modifications of KDM4A

Article

Author: Wang, Yue ; Tang, Wanfen ; Yu, Shian ; Xu, Wenxia ; Ni, Yuqi ; Fu, Junhao ; Fu, Jianfei ; Hu, Yuqing

ABSTRACTGastric cancer is a common digestive system tumor with a high resistance rate that reduces the sensitivity to chemotherapy. Nutrition therapy is an important adjuvant approach to favor the prognosis of gastric cancer. Dietary amino acids contribute greatly to gastric cancer progression by mediating tumor gene expressions, epigenetics, signal transduction, and metabolic remodeling. In the present study, 20 types of amino acids were screened and glutamine, glycine and serine were identified as the critical regulators of cisplatin (DDP) sensitivity in gastric cancer cells. Moreover, KDM4A acetylation drove the reduced chemotherapy sensitivity in gastric cancer cells by maintaining protein stability and activating DNA repair ability when the concentrations of glutamine (Gln), serine (Ser), and glycine (Gly) decreased. Conversely, Gln/Ser/Gly at increasing concentrations stimulated ubiquitination degradation of KDM4A, which in turn elevated the sensitivity of gastric cancer cells to chemotherapy. Our findings unveiled the role of amino acid nutrition in regulating chemotherapy sensitivity of gastric cancer and the underlying mechanism, thus providing a scientific basis for expanding the clinical significance of nutrition therapy for gastric cancer patients.

01 Apr 2025·European Journal of Medicinal Chemistry

Discovery of a first-in-class PROTAC degrader of histone lysine demethylase KDM4

Article

Author: Xu, Shilin ; Yu, Lei ; Zhang, Zhang ; Ren, Ran ; Lai, Yuanhui ; Yang, Xiaolong ; Chen, Zhiwen ; Peng, Lijie ; Sun, Yaoliang ; Rao, Danni ; Wang, Yiting ; Wu, Feifei

Targeting histone lysine demethylase 4 (KDM4) has emerged as a promising approach for cancer therapy. Despite significant progress in developing KDM4 inhibitors, many of these compounds demonstrate poor selectivity or limited cellular efficacy, and none have received approval for marketing. In this study, we designed and synthesized a series of novel KDM4-targeted proteolysis targeting chimeras (PROTAC) degraders, as exemplified by compound 11 (RDN8011). RDN8011 effectively degrades KDM4A-C while sparing KDM4D, and displays potent antiproliferative activity in esophageal cancer cells. Furthermore, this compound inhibits histone H3 lysine demethylation and induces cell cycle arrest and apoptosis. Collectively, this study provides a valuable chemical tool for exploring the functions of KDM4, and presents a novel effective strategy for targeting KDM4 in cancer treatment.

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KDM4A

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