KDM4A

Official Full Name

lysine demethylase 4A

Organism

Homo sapiens

GeneID

9682

Background

This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein containing a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form, and as a transcriptional repressor. [provided by RefSeq, Apr 2009]

Synonyms

JMJD2; JHDM3A; JMJD2A; TDRD14A;

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Detailed Information

Recent Research

The KDM4A gene belongs to the Jumonji domain 2 (JMJD2) family and encodes a protein that contains the JmjC and JmjN domains to form a composite active site, two phd-type zinc finger domains, and two mixed Tudor bilobal domain forms, similar to a normal Tudor domain in each leaf. In vitro, this enzyme can demethylate di- and trimethylated residues at lysines 9 and 36 of histone 3 (H3K9me3/2 and H3K36me3/2, respectively), but this enzyme cannot demethylate monomethylated residues; in vivo, however, KDM4A demethylates only trimethylated residues. KDM4A is considered as a transcription regulator for gene activation or inhibition. In addition to transcription, KDM4A is involved in several other molecular processes, such as DNA damage response, DNA replication, and site-specific replication gain.KDM4A was associated with replication time and genomic stability. In caenorhabditis elegans, KDM4A appears to be involved in the reduction of H3K36me3 on the X chromosome, suggesting a role of this protein in germ cell development. KDM4A also has a close relationship with cancer, which regulates the proliferation of cancer cells. In some studies, KDM4A can also be used as a regulatory factor to promote organ development.

Figure 1. The KDM4A demethylase protein structure

KDM4A is a key regulator of tumor metabolism and plays a functional role in controlling tumor metabolism. KDM4A binds to E2F1 on target gene promoters to enhance E2F1 chromatin binding and transcriptional activity, thereby regulating the transcriptional spectrum essential for cancer cell proliferation and survival. Pyruvate dehydrogenase kinases PDK1 (phospho-inoside-dependent kinase-1) and PDK3 (phospho-inoside-dependent kinase-3) are direct targets of KDM4A and E2F1, which regulate the conversion between glycolysis metabolism and mitochondrial oxidation. Down-regulation of KDM4A leads to increased pyruvate dehydrogenase activity and mitochondrial oxidation, leading to excessive accumulation of reactive oxygen species. Altered metabolic phenotypes were partially salvaged by ectopic expression of PDK1 and PDK3, suggesting kdm4a-dependent regulation of tumor metabolism through PDK.

KDM4A can inhibits AR (Androgen receptor) signaling cascade in AN3CA cells (human endometrial adenocarcinoma cells), which is a relatively low AR level. KDM4A and AR were recruited into the pro-regulatory elements of AR target gene p27kip1 (cyclin-dependent kinase inhibitor 1B), and the expression of tumor suppressors was inhibited by H3K4me3 demylation. This inhibition of p27kip1 increased the proliferation and metastasis of AN3CA cells.

KDM4A is involved in cell proliferation regulation, overexpressed in some cancers, interacts with RNA polymerase I, and binds to the active ribosomal RNA gene, which is required for serum-induced rDNA transcriptional activation. PI3K is a major signal transduction factor for cell proliferation and survival, and regulates the localization of KDM4A cells and its relationship with ribosomal DNA through the downstream kinase of SGK1 (serine/threonine protein kinase). Thus, the interaction between the PI3K/SGK1 signaling cascade and KDM4A constitutes the mechanism by which cells adapt to ribosomal biogenesis levels to accommodate growth factors and nutrient availability.

KDM4A is also an important epigenetic regulator for the differentiation of mESC into endothelial cells in mice, and it also promotes the vascular development of zebrafish. KDM4A initiates differentiation by targeting the Flk1 (kinase insertion domain receptor) promoter. KDM4A acts independently through histone demethylation to induce endothelial cell senescence.

References:

Johmura Y, et al. SCFFbxo22-KDM4A targets methylated p53 for degradation and regulates senescence. Nature Communications, 2016, 7:10574.
Wang B, et al. Downregulation of KDM4A Suppresses the Survival of Glioma Cells by Promoting Autophagy. Journal of Molecular Neuroscience, 2016, 60(2):137-144.
Jie H, et al. Cloning of KDM4A Gene and Its Expression in Different Tissues,Oocyte and Granulosa Cell of Yak. Chinese Journal of Animal and Veterinary Sciences, 2018.
Wang L Y, et al. KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis. Cell Reports, 2016, 16(11):3016-3027.

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