Cancer treatment of the future: Inhibitors of histone methyltransferases

doi:10.1016/j.biocel.2008.07.024

The International Journal of Biochemistry & Cell Biology

Volume 41, Issue 1, January 2009, Pages 4-11

https://doi.org/10.1016/j.biocel.2008.07.024 Get rights and content

Abstract

Cancer in humans is the result of a multi-step process. This process often involves the activation of oncogenes and/or the inactivation of tumor suppressor genes. These two steps arise not only due to mutations, but can also be the result of a translocation or an altered transcription rate. One important mechanism is the occurrence of epigenetic alterations like promotor methylation (which may lead to tumor suppressor silencing) or decreased histone acetylation (which can result in the downregulation of proteins involved in apoptosis). Today, histone acetylation and DNA methylation are epigenetic modifications which have been linked closely to the pathology of human cancers and inhibitors of both enzyme classes for clinical use are at hand. In contrast, other fields of epigenetics still lack of similarly thorough knowledge. This is especially true for the group of histone methyltransferases and their inhibitors. Since connections between histone methylation patterns and cancer progression have been recognized, histone methyltransferases represent promising targets for future cancer treatment.

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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Molecules in focusCancer treatment of the future: Inhibitors of histone methyltransferases

Abstract

Introduction

Section snippets

Protein methylation

Histone methyltransferases

Histone demethylation

Histone methyltransferase inhibitors

Structural aspects of histone methyltransferases with regard to inhibitor design

Conclusions

The emerging functions of histone demethylases

Curr Opin Genet Dev

New nomenclature for chromatin-modifying enzymes

Cell

Expression of four histone lysine-methyltransferases in parotid gland tumors

Anticancer Res

EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast

J Clin Oncol

Arginine methylation an emerging regulator of protein function

Mol Cell

Arginine methylation at a glance

J Cell Sci

Covalent modifications of histones during development and disease pathogenesis

Nat Struct Mol Biol

Epigenetics—an epicenter of gene regulation: histones and histone-modifying enzymes

Angew Chem Int Ed Engl

Arginine methylation of MRE11 by PRMT1 is required for DNA damage checkpoint control

Genes Dev

Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B′ and the Sm-like protein LSm4, and their interaction with the SMN protein

RNA

EZH2 promotes proliferation and invasiveness of prostate cancer cells

Prostate

JMJD6 is a histone arginine demethylase

Science

Expression of nitric oxide related enzymes in coronary heart disease

Basic Res Cardiol

Small molecule regulators of protein arginine methyltransferases

J Biol Chem

The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing

Mol Cell

Protein arginine-methyltransferase-dependent oncogenesis

Nat Cell Biol

Control of CBP co-activating activity by arginine methylation

EMBO J

Regulation of p53 activity through lysine methylation

Nature

The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3

Nature

Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer

Clin Cancer Res

Mechanisms of disease: biomarkers and molecular targets from microarray gene expression studies in prostate cancer

Nat Clin Pract Urol

Histone deimination antagonizes arginine methylation

Cell

A glycine-arginine domain in control of the human MRE11 DNA repair protein

Mol Cell Biol

Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues

Cancer Res

CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1

Cancer Res

Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9

Nat Chem Biol

SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells

Nat Cell Biol

Enhanced SMYD3 expression is essential for the growth of breast cancer cells

Cancer Sci

New therapeutic targets in cancer: the epigenetic connection

Clin Transl Oncol

Mechanisms of transformation by MLL

Crit Rev Eukaryot Gene Expr

Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status

Cancer

p53 is regulated by the lysine demethylase LSD1

Nature

The emerging field of dynamic lysine methylation of non-histone proteins

Curr Opin Genet Dev

Association of the SUV39H1 histone methyltransferase with the DNA methyltransferase 1 at mRNA expression level in primary colorectal cancer

Int J Cancer

The nucleosome: from genomic organization to genomic regulation

Cell

Molecules in focus
Cancer treatment of the future: Inhibitors of histone methyltransferases