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Anticancer activities of histone deacetylase inhibitors

Key Points

  • Histone deacetylase inhibitors are novel anticancer agents that induce tumour cell death, differentiation, and/or cell cycle arrest. As well as their intrinsic effects on tumour cells, histone deacetylase inhibitors may additionally affect neoplastic growth and survival by regulating host immune responses and tumour vasculature.

  • The pleiotropic cellular effects of HDACi can act cooperatively to mediate potent anti-tumour activities; however, the molecular processes underlying these effects of HDACi remain to be fully elucidated.

  • The activity of diverse non-histone proteins can be regulated by acetylation indicating that HDACi may have a much broader effect on cellular physiology than originally understood. Altered gene expression through the effects of HDACi on the activity of transcription factors and transcription-independent effects of HDACi are also important in their anticancer activities.

  • In preclinical studies, several classes of HDACi have been found to have potent anticancer activities, and some have demonstrated promising therapeutic potential in early clinical trials for haematological malignancies such as cutaneous T-cell lymphoma, myelodysplastic syndromes and diffuse B-cell lymphoma.

  • While HDACi show promise as single agent anticancer drugs, their use in combination with other agents may prove to be their most useful application. Already, HDACi have been shown to function synergistically with a host of structurally and functionally diverse chemical compounds and biologically active polypeptides.

Abstract

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.

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Figure 1: Histone deacetylase inhibitors lower the apoptotic threshold of tumour cells.
Figure 2: Effects of histone deacetylase inhibition on non-histone proteins.

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Acknowledgements

We apologise to those whose work was not cited or discussed due to space limitations. We thank R. Lindemann and other members of the Johnstone laboratory for helpful discussions. R.W.J. is a Pfizer Australia Research Fellow and is supported by the National Health and Medical Research Council of Australia, the Cancer Council Victoria and the Leukaemia Foundation of Australia. J.E.B. is supported by The Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology.

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Correspondence to Ricky W. Johnstone.

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The Johnstone laboratory receives research funding from Merck and Novartis.

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FURTHER INFORMATION

Clinical Trails Homepage

Glossary

Tumour-suppressor gene

Genes that inhibit cell-cycle progression or induce apoptosis to regulate cell numbers. Often mutated or functionally inactivated in cancer.

Oncogene

A normal gene that stimulates appropriate cell growth under normal conditions. When mutated or overexpressed, oncogenes can induce the uncontrolled proliferation of cells in the absence of growth signals and mediate neoplastic transformation.

Epigenetic

Reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA.

Remodelling of chromatin

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.

Apoptosis

Also termed programmed cell death, apoptosis is characterized morphologically by membrane blebbing, chromatin condensation, loss of cell volume and DNA fragmentation, and biochemically by caspase activation.

Chromosomal translocation

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.

RARα

Retinoic acid receptor-α.

PML

Promyelocytic leukaemia.

PLZF

Promyelocytic leukaemia zinc finger.

AML1

Acute myeloid leukaemia 1.

ETO

Eight twenty one protein.

Leukaemia

Chronic or acute haemopoietic cancer 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.

Short interfering RNA

(siRNA). A class of 20–25 nucleotide-long RNA molecules that interfere with the expression of a specific gene.

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.

TRAIL

TNF-related apoptosis-inducing ligand.

APAF1

Apoptotic peptidase activating factor.

HTRA2

High-temperature requirement protein A2.

SMAC

Second mitochondria-derived activator of caspase.

MCL1

Myeloid cell leukaemia sequence 1.

Reactive oxygen species

(ROS). Include oxygen ions, free radicals and peroxides (both inorganic and organic) that are highly reactive because of the presence of unpaired valence shell electrons. ROS form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signalling. During times of environmental stress ROS levels can increase dramatically, which can result in significant damage to cell structures.

Checkpoint

A point at which the cell cycle can be halted until conditions are suitable for the cell to proceed to the next stage.

Heterochromatin

Areas of a chromosome that are genetically silent because they either lack genes or contain genes that are hypoacetylated and transcriptionally repressed.

Angiogenesis

The growth of new blood vessels from pre-existing ones. Angiogenesis is a complex phenomenon that is absolutely required for the continued growth and survival of solid neoplasms.

TIMP

Tissue inhibitor of MMP.

RECK

Reversion-inducing cysteine-rich protein with kazal motifs.

Metastasis

A secondary cancerous growth formed by transmission of cancer cells from a primary growth located elsewhere in the body usually by way of blood vessels or lymphatics.

Graft-versus-host disease

An immune reaction of transplanted cells against host tissues that possess an antigen not possessed by the donor.

IC50

The half maximal inhibitory concentration. Represents the concentration of an inhibitor that is required for 50% inhibition of a biological or molecular process.

Caspases

A family of cysteine proteases that cleave a variety of cellular substrates leading to the morphological changes associated with apoptosis. Caspases can also activate inflammatory cytokines such as IL-1.

Proteasome

A barrel-shaped multi-protein complex that can specifically digest ubiquitinylated proteins into short polypeptides and amino acids in an ATP-dependent manner.

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Bolden, J., Peart, M. & Johnstone, R. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5, 769–784 (2006). https://doi.org/10.1038/nrd2133

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