KDM4C

Official Full Name

lysine demethylase 4C

Organism

Homo sapiens

GeneID

23081

Background

This gene is a member of the Jumonji domain 2 (JMJD2) family. The encoded protein is a trimethylation-specific demethylase, and converts specific trimethylated histone residues to the dimethylated form. This enzymatic action regulates gene expression and chromosome segregation. Chromosomal aberrations and changes in expression of this gene may be found in tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

Synonyms

GASC1; JHDM3C; JMJD2C; TDRD14C;

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Detailed Information

Recent Research

KDM4C, also known as JMJD2C, is a member of the KDM4 subgroup containing the JmjC domain, which catalyzes the demethylation of trimethyllysine 9 and lysine 36 on histone H3. KDM4C was first identified as an oncogene amplified in the esophageal cancer cell line KYSE-150. Amplicons of the KDM4C gene were detected in esophageal squamous cell carcinoma, myeloblastoma, breast cancer, b-cell lymphoma, and Hodgkin's lymphoma. In addition, KDM4C has the ability to maintain self-renewal and differentiation of embryonic stem cells, suggesting the importance of KDM4C for early development and stem cell regulation. On the other hand, KDM4C has a new role in regulating the division of mitotic chromosomes. KDM4C protein levels are critical for proper chromosome segregation.

KDM4C is mainly expressed in neurons after mitosis and is not expressed in NSCs in vivo. Furthermore, the expression of the KDM4C gene in astrocytes is unclear. KDM4C subtype mutant mice exhibit abnormal behavior (overactivity, persistence, and learning and memory deficits), and synaptic dysfunction indicates that KDM4C played an important role in brain development. Certain phenotypes of KDM4C low-profile mutant mice are similar to those of neurodevelopmental disorders including autism spectrum disorder (ASD). The authors observed an increase in spinal cord density in KDM4C subtype mutant mice and an increase in spinal cord density in ASD patients. In human ASD patients, GWAS reported copy number changes and single nucleotide polymorphisms at the 9p24.1 locus, including the KDM4C gene.

KDM4C and G9a (H3K9-methyltransferase) is a novel enhancer associated factors, and implicate KDM4C as a molecular scaffold for the assembly of essential enhancer protein complexes with an impact on timely gene activation. Jmjd2 H3K9 demethylase synergistically promotes the identification of mouse embryonic stem cells (ESC). In the absence of KDM4C, differentiation of embryonic stem cells is severely impeded in the early stage of blastocyst formation after implantation. Although ESCs knocked out of kdm4c can be converted to self-renewing EpiSCs, these cells are unable to form three primary germ layer derivatives due to the inability to initiate appropriate gene expression programs. Functionally, ESCs require KDM4C to initiate appropriate gene expression programs during somatic multi-lineage differentiation. The kdm4c binding enhancer is co-occupied with h3k9-methyltransferase G9a (also known as Ehmt2) and is independent of h3k9 modification activity. Deletion of KDM4C disrupts the recruitment of G9a and further disrupts the mediator and the aggrecan component Med1 (mediator protein complex subunit 1) and Smc1 (human pleural tumor cell). They are in esc-derived omental-like cells as the newly activated and stabilized enhancer.

KDM4C activity is important for triple-negative breast cancer, which is directly associated with the growth of the most aggressive form of breast cancer, represented by three triple-negative carcinoma cell lines. The activity of KDM4C is a high requirement for the correct separation of chromosomes during mitosis of these cancer cells. KDM4C demethylation of H3K9-3me is a key process for maintaining chromosome stability in triple negative breast cancer. The micronucleus of certain cell lines can be restored by daughter cells. KDM4C, as part of a complex linkage between mitotic defects, aneuploidy, and chromosomal instability, plays a special role in properly isolating DNA content. KDM4C’s activity is highly required for the correct segregation of chromosomes during mitosis in these cancer cell lines, which strongly supports the potential of KDM4C as a promising therapeutic target for new inhibitors and strategies against the main cause of cancer death in women worldwide.

References:

Kupershmit I , et al. KDM4C (GASC1) lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during mitosis. Nucleic Acids Research, 2014, 42(10):6168-6182.
Lizcano F , et al. KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer. Breast Cancer: Basic and Clinical Research, 2016:169.
Zhao E , et al. KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism. Cell Reports, 2016, 14(3):506-519.
Wu L , et al. Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells[J]. Stem Cell Reports, 2015, 5(1):10-21.
Leurs U , et al. Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C. ACS Chemical Biology, 2014, 9(9):2131-2138.

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