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Histone Demethylases

Histone methylation at lysine and arginine residues is crucial covalent histone modifications in epigenetic regulation. They together with DNA methylation constitute hallmarks of epigenetic inheritance. Histone modifications have been suggested to be part of a ‘code’ which is read by proteins via specific binding domains, and in this way translated into a functional signal. Thus histone modifications can influence chromatin condensation, and poise genes for either transcriptional repression or activation, depending on how the modification is read and translated in a specific context. While individual histone marks have been correlated with either active or silenced transcriptional states, many modifications have several, seemingly opposing roles, and the combination of marks, as well as their genomic context, appear to be crucial for the biological output.

The more recent discovery of histone demethylases made a significant influence on the perception of histone methylation as permanent, inheritable marks supporting more dynamic roles in gene regulation. Thus far, two classes of histone demethylases have been identified. The proteins of the KDM1 (Lysine (K) Demethylase 1) family are FAD-dependent amine oxidases, which can act only on mono- and dimethylated lysines. The Jumonji C (JmjC) domain is a signature motif for the other class of demethylases, which are Fe (II) and 2-oxoglutarate-dependent enzymes. Based on sequence homology in the JmjC domain and the overall architecture of associated motifs, JmjC domain-containing proteins have been classified into different groups, several of which have been found to possess histone demethylase activity (Figure 2).

The demethylase families.Figure 1. The demethylase families.

KDM1 family

KDM1 (LSD) family is composed of two members, KDM1A and KDM1B. KDM1A, also referred to as lysine-specific demethylase 1 (LSD1), was first described in 2004. This protein was found to be a highly conserved flavin-containing amino oxidase homolog that specifically removed the mono- and di-methylated lysine at lysine 4 or lysine 9 of H3, depending on the cellular context. KDM1A contains a SWIRM domain, which has been identified in chromatin-modifying proteins. The other KDM1 family member, KDM1B (also known as LSD2 and AOF1) has so far only been shown to demethylate H3K4me1 and H3K4me2. Both LSD1 and LSD2 use a flavin adenine dinucleotide (FAD)--dependent amine oxidation reaction5 to catalyze the demethylation of their substrate (Figure 2). Because of the requirement of a free electron pair at the methylated Lys residue, LSD1 can only demethylate mono- and dimethylated, but not trimethylated, Lys residues. LSD1, by itself, can demethylate only histones or histone peptides in vitro, but in complex with the neuronal silencer co-repressor of RE1‑silencing transcription factor (CoREST; also known as RCOR1), it can also demethylate histones within nucleosome substrates. This suggests that LSD1 depends on protein partners for its activity in vivo.

Histone demethylation mediated by an LSD (KDM1) family demethylase. Figure 2. Histone demethylation mediated by an LSD (KDM1) family demethylase.

JMJC demethylases

Members of the second family of histone demethylases, which contain the catalytic JMJC domain, were isolated independently in some different laboratories. F-box and Leu-rich repeat protein 11 (FBXL11; also known as JHDM1A and KDM2A) was the first to be published as an H3K36me1 and H3K36me2 histone demethylase. This was followed shortly after by reports of demethylases capable of demethylating trimethylated histone residues. On the basis of homology, the JMJC family consists of 30 members, and so far 18 of these have been shown to possess histone demethylase activity. Within the JMJC family of proteins, demethylases with activity towards H3K4, H3K9, H3K27, H3K36 and H4K20 have been identified. As the name suggests, all family members share a JMJC domain and, depending on the degree of homology and the presence of other domains, they can be further classified into subfamilies that often share substrate specificity. The demethylase reaction catalyzed by this family of proteins is a dioxygenase reaction that depends on Fe (II) and α‑ketoglutarate (Figure 3). It is the different nature of this reaction that allows the JMJC family of enzymes, in contrast to the KDM1 family, to demethylate trimethylated Lys residues.

Histone demethylation mediated by a JMJC domain family demethylase. Figure 3. Histone demethylation mediated by a JMJC domain family demethylase.

Role of histone demethylases in diseases

Given their diverse functions in transcriptional activity, it is no surprise that alteration and aberrant expression of histone demethylases have been noted in many cancers. KDM1A overexpression has also been found in poorly differentiated neuroblastoma. KDM1A can prevent the differentiation process and maintain the malignant phenotype in neuroblastoma, maybe through gene silencing via the REST/CoREST complex. KDM1A is a crucial effector of the differentiation block in MLL-AF9 leukemia. Inhibition of the KDM1A demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. One study indicates that KDM1A is a subunit of the NuRD complex and targets the metastasis programs in breast cancer.

Ectopic expression of either KDM2A or KDM2B results in immortalization of mouse embryonic fibroblasts via the promotion of RB phosphorylation. KDM2A promotes lung tumorigenesis through epigenetically enhancing ERK1/2 signaling. KDM2B is upregulated in leukemic stem cells and is essential in their neoplastic transformation. Increased KDM2B in pancreatic cancers correlates to poorer prognosis and increased tumor aggression. In humans, amplifications, mutations, or deletions of other histone demethylase genes have also been associated with cancer development and aggressiveness, and FBXL10, JMJD2A, JMJD2B, JMJD2C and JARID1B demethylases have been suggested as possible targets for cancer therapy. Moreover, several demethylases have been linked to neural development and/or function. For instance, links have been made between mutations in JARID1C (also known as SMCX and KDM5C), which encodes an H3K4me2 and H3K4me3 demethylase, and X‑linked mental retardation and autism. This is in agreement with earlier studies using cell culture and zebrafish models that have shown a requirement for JARID1C in neuronal survival and dendritic development.

KDM inhibitors

Some types of KDM1A inhibitors have been proposed. Polyamine analogs and substrate analogs were developed to target the catalytic domains of KDM1A. Oligoamine analogs were found to induce re-expression of aberrantly silenced genes in HCT116 cells. Moreover, a highly specific, non-competitive KDM1A inhibitor, HCI-2509 (SP2509), has been effective in inducing apoptosis in Ewing sarcoma cell lines, particularly those that express the EWS-FLI1 fusion protein, alone and in combination with other anticancer agents. Despite the limited number of studies, histone demethylase inhibitors appear to be promising agents for anticancer therapy. However, these enzymes have shown to have complex biological interactions within the cell, so determining the downstream effects of histone demethylase inhibition in vivo will need to be established.


  1. D'Oto A, et al. Histone demethylases and their roles in cancer epigenetics. Journal of Medical Oncology & Therapeutics, 2016, 1(2):34.
  2. Pedersen M T, Helin K. Histone demethylases in development and disease. Trends in Cell Biology, 2010, 20(11):662.
  3. Lohse B, et al. Inhibitors of histone demethylases. Bioorganic & Medicinal Chemistry, 2011, 19(12):3625-36.
  4. Kooistra S M, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nature Reviews Molecular Cell Biology, 2012, 13(5):297.
  5. Rotili D, Mai A. Targeting Histone Demethylases: A New Avenue for the Fight against Cancer. Genes & Cancer, 2011, 2(6):663-679.
  6. Shi Y G, Tsukada Y. The discovery of histone demethylases. Cold Spring Harbor Perspectives in Biology, 2013, 5(9):1288-1302.
  7. Yang Y, et al. Histone demethylase LSD2 acts as an E3 ubiquitin ligase and inhibits cancer cell growth through promoting proteasomal degradation of OGT. Molecular Cell, 2015, 58(1):47-59.
For research use only. Not intended for any clinical use.

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