Histone lysine demethylases as targets for anticancer therapy

• Published in: Nature reviews. Drug discovery Vol. 12; no. 12; pp. 917 - 930
• Main Authors: Højfeldt, Jonas W., Agger, Karl, Helin, Kristian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2013; Nature Publishing Group
• Subjects: 631/154; 631/208/176; 631/67; Animals; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Biomedicine; Biotechnology; Cancer; Cancer Research; Drug Delivery Systems - methods; Drug therapy; Enzymes; Health aspects; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - chemistry; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - chemistry; Histone Demethylases - metabolism; Humans; Medicinal Chemistry; Molecular Medicine; Neoplasms - drug therapy; Neoplasms - enzymology; Pharmacology/Toxicology; Physiological aspects; review-article; Denmark
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd4154

Key Points 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. Specific patterns of post-translational modifications in chromatin structure are important factors in the regulation of gene expression, and when deregulated they can contribute to diseases including cancer and neurological disorders. Here, Helin and colleagues focus on the role of one class of chromatin-modifier enzymes — the histone lysine demethylases — highlighting their links to cancer and their potential to be therapeutically targeted. 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.