There is strong evidence that members of the histone lysine demethylase families are causally linked to cancer and they are therefore considered as potential targets for small-molecule therapeutics.
Lysine-specific demethylase 1 (LSD1) is required for the maintenance of acute myeloid leukaemia. Jumonji domain-containing protein 2B (JMJD2B), JMJD2C, Jumonji/ARID domain-containing protein 1B (JARID1B) and F-box and leucine-rich repeat protein 10 (FBXL10) are overexpressed in several cancers and are required for the growth of cancer cell lines.
The therapeutic potential of selective demethylase inhibitors has been demonstrated in animal models of cancer through the administration of available demethylase inhibitors or knockdown strategies.
Nonselective amine oxidase inhibitors have been derived to yield potent and selective LSD1 inhibitors, and clinical trials will soon be initiated.
Potent and subfamily-selective Jumonji C (JMJC) domain-containing demethylase inhibitors have emerged and provide optimism that true drug leads targeting this protein family are attainable.
It has recently been demonstrated that the genes controlling the epigenetic programmes that are required for maintaining chromatin structure and cell identity include genes that drive human cancer. This observation has led to an increased awareness of chromatin-associated proteins as potentially interesting drug targets. The successful introduction of DNA methylation and histone deacetylase (HDAC) inhibitors for the treatment of specific subtypes of cancer has paved the way for the use of epigenetic therapy. Here, we highlight key biological findings demonstrating the roles of members of the histone lysine demethylase class of enzymes in the development of cancers, discuss the potential and challenges of therapeutically targeting them, and highlight emerging small-molecule inhibitors of these enzymes.
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We thank M. T. Pedersen and S. Kooistra for critical comments on the manuscript. J.H. was supported by a fellowship from the Villum Foundation. Work in the Helin laboratory is supported by the Danish National Research Foundation (grant number DNRF 82), the Danish Cancer Society, the Danish Council for Strategic Research (grant number 12-110503), the Novo Nordisk Foundation, the Lundbeck Foundation, the European Union's Seventh Framework Programme, the European Research Council (grant number 294666_DNAMET) and the Excellence Programme of the University of Copenhagen.
The authors declare no competing financial interests.
- Next-generation sequencing
A collective term for various technologies that allow high-throughput and low-cost sequencing.
- Exome sequencing
A cheaper alternative to whole-genome sequencing that allows sequencing of all coding genes.
- Histone demethylases
Enzymes that catalyse the demethylation of methyl groups from amino acids in histones. Histone demethylases are often also called lysine demethylases or, in short, KDMs.
- Histone methyltransferases
Enzymes that catalyse the methylation of arginine and lysine residues in histones. The more correct terminology for these proteins is protein arginine methyltransferases (PRMTs) and protein lysine methyltransferases (PKMTs).
A short notation for the methylation status of trimethylated lysine 36 on histone H3. This notation style is used to describe the methylation states of specific residues in a histone tail.
- Protein domains
Parts of a protein with a conserved sequence that can evolve and sometimes function and exist independently of the rest of the protein.
- Catalytic domain
The part of the enzyme where the reaction of the substrate occurs.
A molecule that blocks the activity of a target protein.
A measure of drug activity that is defined as the amount of a compound required to elicit an effect of a given strength.
- Target selectivity
The degree to which a drug can affect a target protein without affecting other proteins. This is an attribute that is difficult to obtain when proteins that are similar to the target protein exist.
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Højfeldt, J., Agger, K. & Helin, K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov 12, 917–930 (2013). https://doi.org/10.1038/nrd4154
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