Alteration of chromatin architecture by means of post-translational modifications of histone tails is an important process for the regulation of gene expression. The coordinated actions of histone-tail acetylation, methylation and phosphorylation, and ATP-dependent chromatin remodelling, allow fine control of gene activation or repression.
Histone acetylation and deacetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylatransferases (HDACs).
In cancer, the molecular processes that lead to inappropriate expression of genes due to altered chromatin structure are now being identified, and aberrant acetylation of histone tails is strongly linked to carcinogenesis. So, targeting the transcriptional lesions that lead to neoplasia provides an opportunity for therapeutic intervention at the very apex of the transformation process. Such therapies could affect several molecular programmes, and would therefore be more powerful than targeting the end stages of a single disrupted molecular pathway.
HDAC inhibitors are an exciting new class of chemotherapeutic drugs. These agents interact with the catalytic site of HDACs, block substrate access and allow hyperacetylation of histone tails.
The anticancer potential of HDAC inhibitors stems from their ability to affect several cellular processes that are dysregulated in neoplastic cells. Principally, activation of differentiation programmes, inhibition of the cell cycle and induction of apoptosis are the key antitumour activities of HDAC inhibitors. In addition, activation of the host immune response and inhibition of angiogenesis might also have important roles in HDAC-inhibitor-mediated tumour regression in vivo.
Much interest and excitement has been generated following the success of HDAC inhibitors in potently inhibiting tumour progression in rodent models. HDAC inhibitors can mediate histone acetylation in vivo, induce tumour-cell differentiation or apoptosis depending on the cell type, and are associated with minimal toxicity as assessed by weight loss and post-mortem analyses.
Given the success of HDAC inhibitors in preclinical studies, Phase I and II clinical trials using several different inhibitors have now been initiated. These drugs seem to be well tolerated at the doses required to hyperacetylate histones and achieve clinical outcomes, and their use in combination therapies is an area that can be further exploited in the clinic.
The opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) allow gene expression to be exquisitely regulated through chromatin remodelling. Aberrant transcription due to altered expression or mutation of genes that encode HATs, HDACs or their binding partners, is a key event in the onset and progression of cancer. HDAC inhibitors can reactivate gene expression and inhibit the growth and survival of tumour cells. The remarkable tumour specificity of these compounds, and their potency in vitro and in vivo, underscore the potential of HDAC inhibitors as exciting new agents for the treatment of cancer.
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I apologise to those whose work was not cited or discussed due to space limitations. I thank S. Russell, A. Ruefli and members of my laboratory for helpful discussions, and E. Baker for help with Figure 1. R.W.J. is a Wellcome Trust Senior Research Fellow and is supported by the National Health and Medical Research Council of Australia.
<i>Saccharomyces</i> Genome Database
Also termed 'programmed cell death', is a natural physiological process that occurs during disease and development, and is initiated by cells in response to environmental stresses. It is characterized morphologically by membrane blebbing, chromatin condensation, loss of cell volume and DNA fragmentation, and biochemically by caspase activation.
A normal gene that stimulates appropriate cell growth under normal conditions. When mutated or overexpressed, it can induce the uncontrolled proliferation of cells in the absence of growth signals and mediate neoplastic transformation.
- TUMOUR-SUPPRESSOR GENE
A gene that inhibits cell-cycle progression or induces apoptosis to regulate cell numbers. Often mutated or functionally inactivated in cancer.
A change that influences phenotype without altering genotype.
The structural and functional specialization of cells and tissues during development. It occurs by the gradual maturation of cells with specialized structures and functions from unspecialized precursors as a result of changes in gene expression.
- CELL CYCLE
The sequence of stages — mitosis (M), gap 1 (G1), the DNA-synthesis stage (S) and gap 2 (G2) — that an actively growing cell passes through between the time it is formed and the time it divides to give two new cells. During this time, it doubles its cytoplasmic constituents, replicates its DNA and finally divides to give two daughter cells.
The growth of new blood vessels from pre-existing ones. A complex phenomenon that is required for the continued growth and survival of solid neoplasms.
- CHROMATIN REMODELLING
An alteration in chromatin structure that affects the nuclease sensitivity of a region of chromatin. Accomplished by covalent modification of histones and/or the action of ATP-dependent remodelling complexes.
Initially defined by Paul Ehrlich as “the use of a drug to combat an invading parasite without damaging the host”. Now commonly refers to the treatment of cancer using drugs that are selectively toxic for the cancerous cells.
- CHROMOSOMAL TRANSLOCATION
A genetic rearrangement in which part of a chromosome is detached and transferred to another chromosome, or to another portion of the same chromosome. Reciprocal translocation is when two chromosomes exchange DNA.
A chronic or acute haematopoietic cancer that is characterized by unrestrained growth and loss of differentiation of leukocytes and their precursors. Leukaemia is classified according to the dominant cell type and severity of the disease.
- ZINC FINGER
A protein domain that contains two invariant cysteine, and two invariant histidine, residues that bind a single zinc atom. These domains often confer the DNA-binding component of transcription factors, but can mediate protein–protein interactions.
The study of the metabolism and action of drugs, with particular emphasis on the time that is required for absorption, duration of action, distribution in the body and method of excretion.
The rate and extent to which an active drug enters the general circulation, thereby permitting access to the site of action. Determined by measuring the concentration of the drug in body fluids, or by the magnitude of the pharmacological response.
- DIFFERENTIAL DISPLAY
A method for identifying differentially expressed genes using anchored oligo-dT and random oligonucleotide primers and polymerase chain reaction (PCR) on reverse-transcribed RNA from different cell populations. The amplified complementary DNAs are displayed, and comparisons are drawn between the different cell populations.
- DNA MICROARRAY
A high-throughput, differential gene-expression screen of complementary DNA or oligonucleotide libraries that are printed in extremely high density on microchips. These microchips are probed with a mixture of fluorescently tagged cDNAs that are produced from two different cell populations, and analysed with a laser confocal scanner.
A point at which the cell cycle can be halted until conditions are suitable for the cell to proceed to the next stage.
A structural feature of the chromosome to which microtubules of the mitotic spindle attach.
A family of cysteine proteases that cleave various cellular substrates, which leads to the morphological changes that are associated with apoptosis. Might also activate inflammatory cytokines such as interleukin-1.
An RNA-containing enzyme complex that extends chromosome ends (telomeres) by copying its RNA sequence repeatedly into chromosomal DNA.
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Johnstone, R. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1, 287–299 (2002). https://doi.org/10.1038/nrd772
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