The International Journal of Biochemistry & Cell Biology
Molecules in focusCancer treatment of the future: Inhibitors of histone methyltransferases
Introduction
In eukaryotic cells genes occur in complexes with core histones and other chromosomal proteins to establish the chromatin. The core particle of chromatin is the nucleosome, a nucleoprotein construct that consist of 147 base pairs of DNA folded around an histone octamer; a pair of H2A, H2B H3 and H4 each (Khorasanizadeh, 2004). The histone N-termini, which are rich in arginine and lysine residues, protrude out of the histone octamers and undergo many types of post-translational modifications, such as acetylation, methylation, phosphorylation, ubiquitinylation or sumoylation (Schäfer and Jung, 2005). The extent of chromatin condensation is regulated in part through these modifications which have an impact on gene transcription and the maintenance of altered transcription after cell division (Biel et al., 2005).
Today, histone acetylation is among the best-understood modifications. The level of histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Yang and Seto, 2007, Minucci and Pelicci, 2006). Actively transcribed chromatin shows hyperacetylated regions as compared to heterochromatin, which is not accessible to transcription factors. It has been shown that small inhibitors of HDACs are able to influence the expression of certain genes. Nowadays, HDAC inhibitors are used as drugs for the treatment of cancer (Herranz and Esteller, 2006, Paris et al., 2008). Histone methyltransferases are only emerging now as potential therapeutic targets. This article will provide a comprehensive overview over the known histone methyltransferases and existent links to the pathogenesis of cancer and will present available inhibitors along with an overview of structural data on histone methyltransferases.
Section snippets
Protein methylation
Histone methylation has been shown to play an important role in the regulation of gene-expression patterns. In contrast to histone acetylation, histone methylation does not alter the charge of the histone tail, but influences the basicity, hydrophobicity of histones and their affinity to certain proteins, e.g. transcription factors. The histone methylating enzymes can be subdivided into three classes, SET domain lysine methyltransfeases, non-SET domain lysine methyltransferases and arginine
Histone methyltransferases
So far more than 20 lysine methyltransferases (Qian and Zhou, 2006) and nine arginine methyltransferases (Krause et al., 2007) have been identified in humans and many of them show links to cancer. This will be discussed below for selected examples and an overview is presented in Table 1, Table 2. Lysine methyltransferases traditionally have been termed with individual names. Lately, a common nomenclature for chromatin modifying enzymes has been proposed. The human lysine methyltransferases have
Histone demethylation
The reversal of histone methylation has been described as well. Mono- and dimethylated lysines can be demethylated by an amine oxidase type protein called LSD1 that contributes to transcriptional silencing (Shi et al., 2004). In contrast LSD1 has shown to be a transcriptional activator upon association with the androgen receptor and is therefore considered as a new target for the treatment, e.g. of prostate cancer (Metzger et al., 2005). Trimethylated lysine residues can only be demethylated by
Histone methyltransferase inhibitors
In the field of epigenetics, several enzymes like HDACs or DNA methyltransferases (DNMTs) have been studied extensively for their capability to be inhibited by natural or synthetic compounds. To date, HDAC and DNMT inhibitors are used in cancer therapy or are tested in clinical studies (Kuendgen and Lubbert, 2008).
In contrast to this, the search for inhibitors of histone methyltransferases is still in its infancy. The use of S-adenosylmethionine (SAM) analogues, like methylthio-adenosine, S
Structural aspects of histone methyltransferases with regard to inhibitor design
During the past several years, a variety of crystal structures of histone lysine and arginine methyltransferase in complex with the cofactor analog SAH and/or in complex with peptide substrates have been reported (Bhaumik et al., 2007). However, no three-dimensional structure of a complex between a histone methyltransferase and an inhibitor has been reported so far. Due to the lack of experimental structures a variety of molecular modeling and docking studies have been carried out for histone
Conclusions
Since the field of epigenetics has gained more and more interest, many experiments have been carried out to investigate the still growing number different chromatin modifying enzymes and to highlight their biological and physiological role. Enzymes involved in histone acetylation and DNA methylation serve as current drug targets in the treatment of cancer. For example, the HDAC inhibitor suberoylanilidehydroxamic acid (SAHA) has recently been approved for the treatment of advanced T cell
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