Histone deacetylases

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Abstract

Post-translational modification of the histones of chromatin has a fundamental role in regulating gene expression. Enzymes involved in these epigenetic events include histone deacetylases (class I and class II), which can be inhibited by a structurally diverse group of small molecules. These histone deacetylase inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. Results of clinical trials with several of these agents have indicated that they are well tolerated at doses that have anti-tumour activity.

Introduction

DNA is packaged into nucleosomes — repeating complexes in chromatin composed of approximately 146 base pairs of two superhelical turns of DNA wrapped around an octamer core of pairs of histones H4, H3, H2A and H2B 1., 2.•, 3.•, 4., 5.. The amino-terminal tails of the histones are subject to post-translational modification by acetylation of lysine, methylation of lysine and arginine, phosphorylation of serine and ubiquitination of lysine 3.•, 4., 5., 6.. Histone deacetylases (HDACs) and histone acetyl transferases (HATs) determine the pattern of histone acetylation, which together with other dynamic sequential post-translational modifications might represent a ‘code’ that can be recognised by non-histone proteins forming complexes involved in the regulation of gene expression.

HDACs are also involved in the reversible acetylation of non-histone proteins (e.g. p53, tubulin and various transcription factors). Altered HAT and/or HDAC activities are present in many cancers 7., 8., 9.•.

Several small molecules have been discovered that inhibit class I and class II HDACs. HDAC inhibitors induce cancer cell growth arrest, differentiation and/or apoptosis in vitro and in vivo 10., 11.•. These agents selectively alter the transcription of relatively few of the expressed genes 12., 13., 14., 15., and several HDAC inhibitors are in clinical trials ([11] and below).

Section snippets

Histone deacetylases

Mammalian HDACs have been ordered into three classes (Table 1). Class I deacetylases (HDACs 1, 2, 3 and 8) share homology in their catalytic sites; class II deacetylases include HDACs 4, 5, 6, 7, 9 and 10 16., 17.. HDACs 4, 5, 7 and 9 share homology in two regions: the C-terminal catalytic domain and the N-terminal regulatory domain. HDAC11 contains conserved residues in the catalytic core regions shared by both class I and II mammalian enzymes. HDAC6 and 10 have two regions of homology with

Histone deacetylase inhibitors

HDAC inhibitors (Table 2) can be divided into several structural classes, including hydroxamates, cyclic peptides, aliphatic acids, benzamides and electrophilic ketones.

TSA was the first natural product hydroxamate to be discovered that inhibited HDACs directly [22]. SAHA, which contains relatively less structural complexity, was found to be an inhibitor (at nanomolar concentrations) of partially purified HDAC [23]. Cinnamic acid bishydroxamic acid (CBHA) has been shown to be a potent HDAC

Activity of histone deacetylase inhibitors

HDAC inhibitors cause the induction of differentiation, growth arrest and/or apoptosis in a broad spectrum of transformed cells in culture and tumours in animals, including both haematological cancers and solid tumours [10]. These inhibitory effects are believed to be caused, in part, by accumulation of acetylated proteins, such as nucleosomal histones, which appear to play a major role in regulation of gene transcription 3.•, 4., 5.. A proposed mechanism for the anti-tumour effects of HDAC

Clinical trials

Phase I and II clinical trials with HDAC inhibitors either as monotherapy or in combination with cytotoxics and differentiation agents are ongoing (for review, see [11]).

Clinical trials with PB have involved both intravenous and oral regimens. Evidence of efficacy has been limited and toxicities have included central nervous system symptoms, fatigue and hypocalcemia. PB is in Phase II clinical trials with intravenous dosing. Results with phenyl acetate have been similar to those with PB.

Conclusions

HDAC inhibitors are an exciting new class of drugs that are targeted as anti-cancer agents. These compounds can induce growth arrest, apoptosis and/or terminal differentiation in a variety of solid and haematological neoplasms in patients with advanced disease. Accumulation of acetylated histones in both normal and tumour cells can be used as a marker of biological activity. Hydroxamic acid-based compounds are among the most promising HDAC inhibitors as potential anti-cancer drugs. There is

Update

Considerable progress has been made in defining the biological role(s) of the different HDACs and in demonstrating, firstly, that transformed cells are much more sensitive than normal cells to growth-inhibitory and apoptotic effects of HDAC inhibitors; and secondly, that the expression of relatively few genes are altered in transformed cells treated with HDAC inhibitors (see [52] for following data). Thus, Eric Verdin and colleagues reported that HDAC7 is a regulator of T cell differentiation

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

Memorial Sloan-Kettering Cancer Center and Columbia University jointly hold patents on the hydroxamic acid-based hybrid polar compounds, including SAHA, pyroxamide and CBHA, which are exclusively licensed to Aton Pharma Inc., of which Paul Marks is a founder and member of the Board of Directors. Both institutions and founder have an equity position in Aton Pharma Inc. Research reviewed in this report was supported by grants from the National Cancer Institute (US), The Japan Foundation for the

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