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. 2011 Jun;2(6):663-79.
doi: 10.1177/1947601911417976.

Targeting Histone Demethylases: A New Avenue for the Fight against Cancer

Dante Rotili  1 , Antonello Mai
Affiliations

Targeting Histone Demethylases: A New Avenue for the Fight against Cancer

Dante Rotili et al. Genes Cancer. 2011 Jun.

Abstract

In addition to genetic disorders, epigenetic alterations have been shown to be involved in cancer, through misregulation of histone modifications. Miswriting, misreading, and mis-erasing of histone acetylation as well as methylation marks can be actually associated with oncogenesis and tumor proliferation. Historically, methylation of Arg and Lys residues has been considered a stable, irreversible process due to the slow turnover of methyl groups in chromatin. The discovery in recent years of a large number of histone Lys demethylases (KDMs, belonging to either the amino oxidase or the JmjC family) totally changed this point of view and suggested a new role for dynamic histone methylation in biological processes. Since overexpression, alteration, or mutation of a number of KDMs has been found in many types of cancers, such enzymes could represent diagnostic tools as well as epigenetic targets to modulate for obtaining novel therapeutic weapons against cancer. The first little steps in this direction are described here.

Keywords: 2-oxoglutarate; FAD; Jumonji-containing enzymes; LSD1; cancer.

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Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Schematic representation of H3 and H4 histone tails, with the most important Lys residues involved in mono-, di-, and trimethylation (circles). The most frequent KDM families involved in demethylation of specific methyl markers are shown.
Figure 2.
Figure 2.
Catalytic mechanism of LSD1 (A) and JmjC (B) enzymes.
Figure 3.
Figure 3.
Substrate analogues as LSD1 inhibitors.
Figure 4.
Figure 4.
Proposed mechanism of inactivation of LSD1 by substrate analogue inhibitors.
Figure 5.
Figure 5.
Polyamine analogues as LSD1 inhibitors.
Figure 6.
Figure 6.
Anti-MAO-based LSD1 inhibitors.
Figure 7.
Figure 7.
Proposed structures for the flavin adenine dinucleotide (FAD)–tranylcypromine adducts in the LSD1 complex.
Figure 8.
Figure 8.
Structures of flavin adenine dinucleotide (FAD)–tranylcypromine adducts obtained by the trans-2-PCPA enantiomers.
Figure 9.
Figure 9.
Structures of pomalidomide and lenalidomide.
Figure 10.
Figure 10.
Structures of JmjC KDM inhibitors.
See this image and copyright information in PMC

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