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KDM4A

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KDM4A
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKDM4A, JHDM3A, JMJD2, JMJD2A, TDRD14A, lysine demethylase 4A
External IDsOMIM: 609764; MGI: 2446210; HomoloGene: 27780; GeneCards: KDM4A; OMA:KDM4A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9682

230674

Ensembl

ENSG00000066135

ENSMUSG00000033326

UniProt

O75164

Q8BW72

RefSeq (mRNA)

NM_014663

NM_001161823
NM_172382

RefSeq (protein)

NP_055478

NP_001155295
NP_759014

Location (UCSC)Chr 1: 43.65 – 43.71 MbChr 4: 117.99 – 118.04 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the KDM4A gene.[5][6][7]

Function

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This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein with a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily. It functions as a trimethylation-specific demethylase, converting specific trimethylated histone on histone H3 lysine 9 and 36 residues to the dimethylated form and lysine 9 dimethylated residues to monomethyl, and as a transcriptional repressor.[7]

Alterations in this gene have been found associated with chromosomal instability that leads to cancer.[8]

In humans, the role of Kdm4a as an oncogene, or cancer associated gene, is well established. It is implicated in prostate tumors, where it is overexpressed,[9] and stimulates cell proliferation in colon cancer cells, where it promotes formation of the tumor itself.[10] In lung cancer cell lines, where Kdm4a is also overexpressed, it coordinates with other oncogenes (like Ras) to transform normal cells into cancerous cells by inhibiting tumor suppressor pathways such as p53.[11] Suppression of Kdm4a in breast cancer cell lines has shown to reduce cancer cell proliferation through cell cycle arrest, and decrease tumor migration and invasion.[12]

In mice models, Kdm4a influences various processes leading up to implantation of the embryo.[13] The expression of this gene is observed in all tissues critical to the female reproductive system, including the hypothalamus, pituitary, ovary, oviducts, and uterus, as well as embryonic development. A knockout of this gene in female mice has shown to negatively interfere with maintaining a maternal uterine environment suitable to receive and implant the blastocyst. It also interferes in the early embryonic development of the female mice's pups prior to implantation, leading to infertility. While mechanisms of normal ovulation and fertilization remain unaffected, infertility may also be partly due to decreased levels of Prolactin, a hormone crucial during the process of pregnancy. A knockout of Kdm4a has no effect on the fertility or viability of male pups.[13]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000066135 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033326 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (June 1998). "Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research. 5 (3): 169–76. doi:10.1093/dnares/5.3.169. PMID 9734811.
  6. ^ Katoh M, Katoh M (June 2004). "Identification and characterization of JMJD2 family genes in silico". International Journal of Oncology. 24 (6): 1623–8. doi:10.3892/ijo.25.3.759. PMID 15138608.
  7. ^ a b "Entrez Gene: JMJD2A jumonji domain containing 2A".
  8. ^ Black JC, Manning AL, Van Rechem C, Kim J, Ladd B, Cho J, Pineda CM, Murphy N, Daniels DL, Montagna C, Lewis PW, Glass K, Allis CD, Dyson NJ, Getz G, Whetstine JR (2013). "KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors". Cell. 154 (3): 541–55. doi:10.1016/j.cell.2013.06.051. PMC 3832053. PMID 23871696.
  9. ^ Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Torben A, Hansen KH, Helin K (28 May 2006). "The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3". Nature. 442 (2006): 307–311. Bibcode:2006Natur.442..307C. doi:10.1038/nature04837. PMID 16732293. S2CID 2874903.
  10. ^ Kim TD, Shin S, Berry WL, Oh S, Janknecht R (1 December 2011). "The JMJD2A demethylase regulates apoptosis and proliferation in colon cancer cells". Journal of Cellular Biochemistry. 113 (4): 1368–1376. doi:10.1002/jcb.24009. PMID 22134899. S2CID 25318400.
  11. ^ Mallette FA, Richard S (November 15, 2012). "JMJD2A Promotes Cellular Transformation by Blocking Cellular Senescence through Transcriptional Repression of the Tumor Suppressor CHD5". Cell Reports. 2 (5): 1233–1243. doi:10.1016/j.celrep.2012.09.033. PMID 23168260.
  12. ^ Li BX, Zhang MC, Luo CL, Yang P, Li H, Xu HM, Xu HF, Shen YW, Xue AM, Zhao ZQ (3 Oct 2011). "Effects of RNA interference-mediated gene silencing of JMJD2A on human breast cancer cell line MDA-MB-231 in vitro". Journal of Experimental & Clinical Cancer Research. 30 (2011): 90. doi:10.1186/1756-9966-30-90. PMC 3215938. PMID 21962223.
  13. ^ a b Sankar A, Kooistra SM, Gonzalez JM, Ohlsson C, Poutanen M, Helin K (2017). "Maternal expression of the histone demethylase Kdm4a is crucial for pre-implantation development". Development. 144 (2017): 3264–3277. doi:10.1242/dev.155473. PMID 28827393.

Further reading

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