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Histone-deacetylase inhibitors: novel drugs for the treatment of cancer

Key Points

  • 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.

Abstract

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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Figure 1: Chromatin structure regulates transcriptional activity.
Figure 2: Regulation of cell growth and survival by HDAC inhibitors.
Figure 3: Induction of cell death by HDAC inhibitors.

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Acknowledgements

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.

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DATABASES

Cancer.gov

breast cancer

cervical carcinoma

colorectal cancer

endometrial carcinoma

gastric carcinoma

leukaemia

lung cancer

lymphoma

multiple myeloma

myelodysplastic syndrome

non Hodgkin's lymphoma

oral carcinoma

ovarian carcinoma

pancreatic carcinoma

prostate carcinoma

skin cancer

stomach cancer

LocusLink

ACTR

AIF

AML

androgen receptor

APAF1

APC

ATF2

ATM

BAK

BAX

BCL2

BCL6

BCLX L

BID

BMYB

BRCA1

E-cadherin

caspase-3

caspase-7

caspase-8

caspase-9

caspase-10

β-catenin

CBP

CD40

CD80

CD86

CD95

CD95L

CDK2

CDKN1A

CDKN1B

CDKN2A

CDKN2B

CPA3

cyclin A

cyclin D

cyclin E

cytochrome c

DAPK

DHFR

DNMT1

DNMT3A

DNMT3B

E2F

EKLF

endothelin A receptor

endothelin B receptor

ER

ETO

FADD

GATA1

GATA2

GCN5

gelsolin

GM-CSF

GSTP1

H1

H2A

H2B

H3

H4

HAT1

HBO1

HDAC1

HDAC2

HDAC3

HDAC4

HDAC5

HDAC6

HDAC7

HDAC8

HDAC9

HDAC10

HIF1A

HMG1

HMG14

HMG17

HMGIY

HSP86

HTRA2

ICAM1

IFNB

IFNG

IGFBP3

IL2

IL8

IL10

IRF1

IRF2

LKB1

MAD

MAGE3

MAX

MBD1

MBD2

MBD3

MECP2

MEF2

MGMT

MLH1

MLL

MORF

MOZ

c-MYB

MYC

MYOD

NCOR

NES1

NF-κB

NPM

p53

P107

p300

PAI2

PARP

PCAF

PKCD

PLZF

PML

PU.1

RB

RARα

RARB

RIZ1

RXR

SIRT1

SIRT2

SIRT3

SIRT4

SIRT5

SIRT6

SIRT7

SMAC

SMRT

SOCS1

SRC1

STAT5b

TAFII250

TEL

TERT

TFIID

TFIIE

TFIIF

TGFB1

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thrombospondin 1

TIF2

TIMP3

TIP60

TMS1

TNF receptor

TP73

TRAIL receptor

VEGF

VHL

YY1

Medscape DrugInfo

valproic acid

OMIM

acute lymphoblastic leukaemia

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acute promyelocytic leukaemia

Rubinstein–Taybi syndrome

<i>Saccharomyces</i> Genome Database

Gcn5

Sir2

FURTHER INFORMATION

Boston University School of Medicine

Cancer.gov

Chromatin Network

Greenebaum Cancer Center

Johns Hopkins Oncology Center

Memorial Sloan–Kettering Cancer Center

Mount Sinai Hospital

National Cancer Institute

Ohio State University

Regulation of Gene Expression

Glossary

APOPTOSIS

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.

ONCOGENE

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.

EPIGENETIC

A change that influences phenotype without altering genotype.

DIFFERENTIATION

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.

ANGIOGENESIS

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.

CHEMOTHERAPY

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.

LEUKAEMIA

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.

PHARMACOKINETICS

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.

BIOAVAILABILITY

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.

CHECKPOINT

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

KINETOCHORE

A structural feature of the chromosome to which microtubules of the mitotic spindle attach.

CASPASES

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.

TELOMERASE

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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