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Histone deacetylases and cancer: causes and therapies

Key Points

  • Histone acetylation is determined by the activities of two classes of enzyme: histone acetyltransferases (HATs) and histone deacetylases (HDACs).

  • Histones are the core protein components of nucleosomes and their acetylation status regulates, in part, gene expression.

  • Deacetylated histones are generally associated with silencing gene expression; so the acetylation of histones is generally associated with derepression of gene expression.

  • Aberrant acetylation is associated with several solid tumours and haematological malignancies.

  • Several types of compound have been identified that inhibit HDACs and cause accumulation of acetylated histones in normal and tumour tissues. They also inhibit transformed cell growth in vitro and in vivo.

  • Inhibition of HDACs with hydroxamic-acid-based hybrid polar compounds — for example, suberoylanilide hydroxamic acid (SAHA) — alters transcription of very few expressed genes.

  • Several HDAC inhibitors are in clinical trials with cancer patients. They are well tolerated, cause accumulation of acetylated histones in peripheral mononuclear cells and tumours and, more importantly, have clinical activity with objective tumour regression.

Abstract

Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?

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Figure 1: Schematic of the structure of histones in nucleosomes.
Figure 2: Proposed mechanism of action of histone deacetylase inhibitors.
Figure 3: Structure of SAHA bound to an HDAC-like protein.

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Acknowledgements

Memorial Sloan–Kettering Cancer Center and Columbia University jointly hold the patents on the hydroxamic-acid-based hybrid polar compounds, including SAHA, pyroxamide, CBHA and related compounds, which are exclusively licensed to Aton Pharma, Inc., of which P.A.M., R.A.R., V.M.R. and R.B. are founders. Both Institutions and the founders have an equity position in Aton Pharma, Inc. The research in the authors' laboratories reviewed in this article were supported, in part, by grants from the National Cancer Institute, The Japan Foundation for the Promotion of Cancer Research, the DeWitt Wallace Fund for the Memorial Sloan–Kettering Cancer Center, The Kleberg Foundation and CaPcure. We are grateful to M. Miranda and M. Corrigan for assistance in preparation of this review.

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Correspondence to Paul A. Marks.

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DATABASES

CancerNet:

breast cancer

bladder tumours

Hodgkin's disease

neuroblastoma

non-Hodgkin's lymphoma

ovarian tumours

prostate cancer

stomach cancer

 LocusLink:

AML1

CBP

CDKN1A

CDKN2A

COUP-TF

cyclin E

DNMT1

E2F

ETO

GATA1

gelsolin

H1

H2A

H2B

H3

H4

HDAC1

HDAC2

HDAC3

HDAC4

HDAC5

HDAC6

HDAC7

HDAC8

HDAC9

LAZ3

MOZ

MYOD

p300

p53

PML

RARa

SAS2

TERT

TFIIE

TFIIF

TIF2

TIP60

WAF1

 Medscape DrugInfo:

capecitabine

carboplatin

paclitaxel

valproic acid

 OMIM:

Rubinstein–Taybi syndrome

 Saccharomyces Genome Database:

Hda1

Rpd3

Sir2

Glossary

CHAPS

A type of histone deacetylase inhibitor in which a hydroxamic-acid moiety is linked to a cyclic tetrapeptide analogue of trapoxin.

CpG ISLAND

DNA region of >500 base pairs that has a high CpG density and is usually unmethylated. CpG islands are found upstream of many mammalian genes; methylation leads to transcriptional silencing.

HUS1/RAD9

These proteins were identified by their sensitivity to hydroxyurea and radiation, respectively. They form a complex, involving HDAC1, in G2/M checkpoint control.

CHICKEN OVALBUMIN UPSTREAM PROMOTER TRANSCRIPTION FACTOR

(COUP-TF). An orphan nuclear receptor that represses transcription of many genes and associates with HDACs.

MYELODYSPLASTIC SYNDROME

Considered to be preleukaemic, this syndrome is characterized by disordered haematopoiesis, with a decrease in mature white blood cells, platelets and erythrocytes.

ACUTE MYELOID LEUKAEMIA, M2 SUBTYPE

Classification of acute myeloid leukaemia. The M2 subtype is characterized by predominance of granulated blasts. Differentiaton beyond the promyelocyte stage might be present.

PHASE I CLINICAL TRIAL

A trial designed primarily to evaluate toxicity of a new therapeutic agent and to determine the maximal 'safe' dose.

PHASE II CLINICAL TRIAL

A trial designed to determine if a 'safe' dose of a new therapeutic agent is effective in treating disease.

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Marks, P., Rifkind, R., Richon, V. et al. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1, 194–202 (2001). https://doi.org/10.1038/35106079

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