Key Points
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Histone acetylation is determined by the activities of two classes of enzyme: histone acetyltransferases (HATs) and histone deacetylases (HDACs).
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Histones are the core protein components of nucleosomes and their acetylation status regulates, in part, gene expression.
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Deacetylated histones are generally associated with silencing gene expression; so the acetylation of histones is generally associated with derepression of gene expression.
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Aberrant acetylation is associated with several solid tumours and haematological malignancies.
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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.
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Inhibition of HDACs with hydroxamic-acid-based hybrid polar compounds — for example, suberoylanilide hydroxamic acid (SAHA) — alters transcription of very few expressed genes.
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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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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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Glossary
- CHAPS
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A type of histone deacetylase inhibitor in which a hydroxamic-acid moiety is linked to a cyclic tetrapeptide analogue of trapoxin.
- CpG ISLAND
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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
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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
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(COUP-TF). An orphan nuclear receptor that represses transcription of many genes and associates with HDACs.
- MYELODYSPLASTIC SYNDROME
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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
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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
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A trial designed primarily to evaluate toxicity of a new therapeutic agent and to determine the maximal 'safe' dose.
- PHASE II CLINICAL TRIAL
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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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DOI: https://doi.org/10.1038/35106079
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