KDM1A

Official Full Name

lysine demethylase 1A

Organism

Homo sapiens

GeneID

23028

Background

This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several histone deacetylase complexes, though it silences genes by functioning as a histone demethylase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

Synonyms

AOF2; CPRF; KDM1; LSD1; AIMAH3; BHC110;

Bio Chemical Class

CH-NH donor oxidoreductase

Protein Sequence

MLSGKKAAAAAAAAAAAATGTEAGPGTAGGSENGSEVAAQPAGLSGPAEVGPGAVGERTPRKKEPPRASPPGGLAEPPGSAGPQAGPTVVPGSATPMETGIAETPEGRRTSRRKRAKVEYREMDESLANLSEDEYYSEEERNAKAEKEKKLPPPPPQAPPEEENESEPEEPSGVEGAAFQSRLPHDRMTSQEAACFPDIISGPQQTQKVFLFIRNRTLQLWLDNPKIQLTFEATLQQLEAPYNSDTVLVHRVHSYLERHGLINFGIYKRIKPLPTKKTGKVIIIGSGVSGLAAARQLQSFGMDVTLLEARDRVGGRVATFRKGNYVADLGAMVVTGLGGNPMAVVSKQVNMELAKIKQKCPLYEANGQAVPKEKDEMVEQEFNRLLEATSYLSHQLDFNVLNNKPVSLGQALEVVIQLQEKHVKDEQIEHWKKIVKTQEELKELLNKMVNLKEKIKELHQQYKEASEVKPPRDITAEFLVKSKHRDLTALCKEYDELAETQGKLEEKLQELEANPPSDVYLSSRDRQILDWHFANLEFANATPLSTLSLKHWDQDDDFEFTGSHLTVRNGYSCVPVALAEGLDIKLNTAVRQVRYTASGCEVIAVNTRSTSQTFIYKCDAVLCTLPLGVLKQQPPAVQFVPPLPEWKTSAVQRMGFGNLNKVVLCFDRVFWDPSVNLFGHVGSTTASRGELFLFWNLYKAPILLALVAGEAAGIMENISDDVIVGRCLAILKGIFGSSAVPQPKETVVSRWRADPWARGSYSYVAAGSSGNDYDLMAQPITPGPSIPGAPQPIPRLFFAGEHTIRNYPATVHGALLSGLREAGRIADQFLGAMYTLPRQATPGVPAQQSPSM

Open

Disease

Acute myeloid leukaemia, Alzheimer disease, Ewing sarcoma, Lung cancer, Lymphoma, Malignant haematopoietic neoplasm, Myelodysplastic syndrome, Myeloproliferative neoplasm, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

9 +

Discontinued Drug

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Detailed Information

Recent Research

KDM1A (Lysine-specific histone demethylase 1 A, also known as LSD1) is the first identified lysine specific histone demethylase. The KDMA1 gene contains 19 exons that are highly conserved in vertebrates. By RNA alternative splicing, two additional exons, exon E2a and exon E8a, can be included in the mature mRNA, producing four possible LSD1 isoforms, namely conventional LSD1, LSD1 plus exons E2a (LSD1 + 2a), exon E8a (LSD1 + 8a)) or both (LSD1 + 2a + 8a).KDM1A catalyzes the demethylation of lysine in a flavin adenine dinucleotide (FAD)-dependent oxidation reaction. As a key component of various transcriptional co-repressor complexes, KDM1A selectively removes methyl groups from H3K4me1/2 and mediates gene suppression. During cell cycle progression, KDM1A is hyperphosphorylated in tumor cells. Moreover, the function of KDM1A shows tumor type specificity. In breast cancer, KDM1A is down-regulated and the introduction of KDM1A inhibits metastatic potential in vivo. In contrast, KDM1A is elevated in a variety of cancers, including glioblastoma, and plays an important role in tumor progression.

The current scientific literature points to the key role of KDM1A in the biology of cancer cells, particularly in maintaining the silencing of differentiated genes. KDM1A, in fact, occupies promoters of a portion of proneural genes that contain bivalent domains and chromatin regions containing both H3K4me2/H3K4me3 and H3K27me3 marks, where KDM1A controls the levels of H3K4 methylation in order to keep these genes sile.

In recent years, KDM1A was identified as a potential target for prostate cancer therapy. KDM1A is a histone demethylase that removes monomethyl (me) and dimethyl (me2) labels from K4 or K9 of histone 3 (H3K4 and H3K9, respectively).When associated with the androgen receptor (AR), the enzyme removes repressive methyl marks from H3K9, thereby enhancing AR dependent gene transcription and prostate tumor cell proliferation. Methylation of KDM1A is executed by euchromatic histone-lysine N-methyltransferase 2 (EHMT2) in an androgen-dependent manner and serves as a regulatory switch to allow for interactions with chromodomain-helicase DNA-binding protein 1 (CHD1).

KDMA1 can directly interact with a member of the MYC family proteins (MYCN) in Neuroblastoma (NB) cells and cooperate with MYCN to repress the expression of genes involved in negative regulation of cell proliferation and transformation such as Cyclin-dependent kinase inhibitor 1(CDKN1A/p21) and the putative tumor suppressor gene Clusterin (CLU). The MYCN/KDM1A complex has a direct role in maintaining the epigenetic silencing of dedicated MYCN target genes. Pharmacological inhibition of either MYCN or LSD1 or combination of both drugs has significant effects in neuroblastoma cell cycle and viability partly through activation of apoptosis.

In human glioblastoma specimens, KDM1A levels are correlated with ribose synthase kinase 3 (GSK3β) and ubiquitin-specific peptidase 22 (USP22) levels. KDK1A phosphorylation of GSK3β promotes the binding of KDM1A to USP22, and then goes Ubiquitination, which provides a direct link between substrate phosphorylation and deubiquitination. In addition, the GSK3 inhibitor tideglusib is down-regulated by KDM1A to make tumor xenografts sensitive to chemotherapy in mice and improve survival. Nuclear GSK3 and usp22-mediated KDM1A stabilization is necessary for glioblastoma tumorigenesis. Nuclear GSK3 is responsible for the accumulation of histone demethylase KDM1A and tightly regulates histone H3K4 methylation during tumorigenesis. When CK1 (a member of the tyrosine kinase 1 family) initiates phosphorylation of KDM1A serine 687, GSK3 phosphorylates KDM1A serine 683.Phosphorylation of KDM1A induces its binding to USP22 and deubiquitination, leading to KDM1A stabilization. Stabilization of GSK3 and usp22-dependent KDM1A is necessary for the demylation of histone H3K4, so cancer stem cells self-renew and glioblastoma tumorigenesis.

References:

Zhou A , et al. Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nature Cell Biology, 2016, 18(9):954-966.
Metzger E , et al. Assembly of methylated KDM1A and CHD1 drives androgen receptor–dependent transcription and translocation. Nature Structural & Molecular Biology, 2016, 23(2):132.
Laurent B , et al. A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation. Molecular Cell, 2015, 57(6):957-970.
Tunovic S , et al. De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome. American Journal of Medical Genetics Part A, 2014, 164(7):1744-1749.

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