Elsevier

Cancer Treatment Reviews

Volume 30, Issue 5, August 2004, Pages 461-472
Cancer Treatment Reviews

LABORATORY–CLINIC INTERFACE
Histone deacetylase inhibitors – a new tool to treat cancer

https://doi.org/10.1016/j.ctrv.2004.04.006Get rights and content

Abstract

Transcriptional regulation in eukaryotes is a multilevel hierarchical process. It is becoming clear that higher-order chromatin structure, occurring via modifications of histones in their nucleosome structure, plays a crucial role in regulating gene expression, both in normal and pathological states. Deacetylation of histones by histone deacetylases (HDACs) modifies the chromatin from an open gene active euchromatin structure to a closed gene silenced heterochromatin structure.

Several cancer promoting mutations and chromosomal translocations result in repression of transcription through abnormal recruitment and activation of HDACs, leading to neoplastic transformation. This is the rationale for the evolvement of HDAC inhibitors as a new class in cancer therapy. Trials have shown anti-proliferation effect of histone deacetylase inhibitors in cell culture, animal models and in human with both hematological and solid tumors. The exact mechanism by which histone deacetylase inhibitors exert their effect is still obscure. Reversal of the alteration in gene expression by fusion transcription factors or overexpressed repressors is just one of several possible explanations. The territory of heterochromatin in the vicinity of the nuclear periphery raised the possibility of involvement of nuclear envelope proteins in the regulation of transcription. Our laboratory is interested in the transcription repression mechanism induced by the nuclear envelope lamina associated polypeptide 2 (LAP2) family of proteins through chromatin modification.

Here, we will describe the structure of the nucleosome, review regulation of gene expression by acetylation of histones and give an update on the current phase I and phase II clinical trials with histone deacetylase inhibitors.

Introduction

Although the complete elucidation of the human genome has revealed almost every gene within our DNA, the regulation of gene expression is still a substance of intensive research. Inappropriate or altered gene expression may result in disease states including neoplastic transformation. Therefore, understanding the molecular mechanisms that regulate and control level of gene expression is of great interest. Genomic aberrations, frequently observed in cancer, influence gene expression.1 However, it has become clear that changes in gene expression may occur in the absence of genomic aberrations. Rather changes in chromatin structure through histones modification may result in aberrant gene expression indicating it as a viable clinical target. One such modification is deacetylation of histones, leading to repression of tumor suppressor genes. This is the rationale for using histone deacetylase (HDAC) inhibitors in cancer therapy. Clinical trials have shown the utility of HDAC inhibitors in treatment of both patients with solid tumors and hematological malignancies; however, the accurate mechanisms of these new agents have not yet been adequately defined.

Here, we will review the structure of the nucleosome and how gene expression is regulated by acetylation of histones. Subsequently, we will discuss the group of HDAC inhibitors which have showed anti-proliferative effect in cell cultures, animal models and in human clinical trials.

Section snippets

Nucleosome structure and regulation of gene expression by histones

The nucleosome, a subunit of chromatin, is composed of an average of 150 bp of DNA. Since uncoiled DNA contained by each chromosome would extend to a length of 1.7–8.5 cm, packaging into a condensed structure is required. The DNA is wrapped around a core of histone proteins and together forms the chromatin.2 Each nucleosome contains DNA double helix that surrounds a central core of eight histone protein molecules. The inter-relationships between chromatin remodeling, histone modification, DNA

HDACs and transcriptional repression

Many co-repressors have been identified in the recent years. They play essential roles in differentiation, proliferation, programmed cell death and cell cycle.11 Among them, HDACs are known to regulate chromatin structure through histone modification (the effect of HDAC1 on acetylation of histone H4 is seen in Fig. 2). Although all core histones are acetylated in vivo; modifications of histones H3 and H4 are much more extensively characterized than those of H2A and H2B. Important positions for

Transcriptional repression at the nuclear envelope vicinity

The nuclear periphery is speculated to be an area of gene silencing. The nuclear envelope (NE), the boundary between the nucleoplasm and cytoplasm, is composed of inner and outer nuclear membranes (INM and ONM, respectively), nuclear pore complexes and an underlying mesh-like supportive structure – the lamina.33 The specialized inner membrane contains a group of unique proteins, which maintain close association with the underlying lamina and chromatin.34 NE proteins are now known to be involved

Abnormal activity of HDACs and neoplastic transformation

Aberrant activities of HATs or HDACs due to translocation, amplification, overexpression and/or mutation are known to be involved in the pathogenesis of cancer.48 Although mutations in p300, a closely related HAT protein, were identified in epithelial malignancies,49 silencing of p300 may also be achieved by epigenetic mechanisms such as promoter methylation.50 The gene encodes for CBP, a protein with histones acetylation activity, is known to be mutated in patients with Rubinstein–Taybi

HDACs inhibitors – potential anti-cancer drugs

Recruitment of HDACs for mediating transcriptional repression provides the rationality for using inhibitors of HDAC activity in cancer therapy.59 Several classes of HDACs inhibitors have been identified including: (1) short-chain fatty acid such as butyric acid; (2) hydroxamic acids such as trichostatin A (TSA), suberoylanilide hyroxamic acid (SAHA) and oxamflatin; (3) cyclic tetrapeptides with or without 2-amino-8-oxo-9, 10-epoxy-decanoyl (AOE) and (4) benzamides such as MS-27-275,5 (Table 1).

Conclusions and future prospects

It is now becoming clear that modification of histones and their tails play an important role in neoplastic transformation. Changes in chromatin structure through deacetylation of histones result in aberrant gene expression, thus implying HDACs to be a practicable clinical target therapy. Total inhibition of HDAC was speculated to be toxic for human use, however human clinical trials proven it to be effective, tolerate and with selective toxicity. The reason for that might be the non-potent

Acknowledgements

We thank Paul A. Marks, M.D., from Memorial Sloan-Kettering Cancer Center, New York, USA, for providing us using his excellent figure and table published in Nature Reviews Cancer (1,194-202,2001).

We thank the Arison family for their donation to Pediatric Oncology.

Part of this work was performed in partial fulfilment of the requirements of the PhD degree of Raz Somech, Sackler School of Medicine, Tel Aviv University.

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