Merck UK: Calbiochem - Histone Deacetylases (HDACs)

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Histone Deacetylases (HDACs)

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Gene expression, to a large extent, is controlled by a host of protein complexes that continuously pack and unpack the chromosomal DNA from the inaccessible, tightly packed nucleosomal particles to the accessible, unwound nucleosomal particles. This packing and unpacking is achieved by the acetylation and deacetylation of the histones in the nucleosomal core. Two classes of enzyme affect the acetylation of histones – histone acetyltransferases (HATs) and histone deacetylases (HDACs). The nucleosome contains 146 base pairs of DNA wrapped around the core histone octamer. The histone octamer is composed of two copies of each of H2A, H2B, H3 and H4, highly basic proteins that are well conserved. All four-core histones have a lysine-rich amino-terminal tail, which contains about half of the positively charged residues and most of the post-translational modification sites of the core histones. Histone H1, although an important determinant of DNA condensation, is not regulated by acetylation.

The reversible acetylation of lysine amino groups in nuclear histones is an important mechanism of regulating gene expression. Acetylated histone proteins confer accessibility of the DNA template to the transcriptional machinery for expression. It is suggested that the acetylation of histone-tail lysines is not random; indeed, HATs preferentially acetylate specific histone lysine substrates. Histone acetylation has been linked to gene-specific activation by transcription factors. It plays an important role in cell cycle control and has been linked to the uncontrolled cell proliferation. Histone hyperacetylation is well correlated with increased transcription, whereas hypoacetylation correlates with transcriptional repression.

Histone deacetylases (HDACs) are chromatin remodeling factors that deacetylate histones and act as transcriptional repressors or silencers of genes. They regulate histone acetylation by catalyzing the removal of acetyl groups on the amino terminal lysine residues of the core nucleosomal histones. Each cell is reported to have several different types of HDACs. For example, in the yeast Saccharomyces cerevisiae there are as many as 10 different HDACs that have the potential to control nucleosomal repression of transcription. In humans at least sixteen different HDACs have been reported and are sub-divided into class I (HDAC 1, 2, 3, 8), class II (HDAC 4, 5, 6, 7, and 9), and class III (SIRT 1 to 7).

In addition to acetylation and deacetylation status of histones, another important determinant of human cancers is the DNA methylation pattern. In cancer cells, the amount of methylated cytosine at the genome-level is reported to be significantly low when compared to normal tissues. Also, genes are transcriptionally silenced in human tumors by promoter hypermethylation. DNA methylation can sterically hinder the binding of activating transcription factors to gene promoters. Another silencing mechanism involves the activity of methyl CpG binding domain (MBD) proteins that specifically bind methylated DNA and repress transcription. MBD proteins can also recruit transcriptional co-repressors, including HDACs and Sin3A, to methylated DNA. HDAC inhibitors, such as Trichostatin A are reported to re-activate methylation-silenced tumor suppressor genes.

Studies have shown that certain oncogenes repress transcription by recruitment of HDACs. This has lead to the interest in small molecules that act as inhibitors of HDAC and have potential for the treatment of cancer. They act as potent inducers of growth arrest, differentiation, and apoptotic cell death in a variety of transformed cells in culture and in tumor bearing animals. They are shown to increase the DNA-binding activities of AP1, CREB and NF-kB transcription factors. The best-studied inhibitors of HDAC is Trichostatin A, a hydroxamic acid that complexes with zinc at the catalytic and mediates the acetamide cleavage at the catalytic site. HDAC inhibitors are also reported to down-regulate telomerase activity via suppression of hTERT mRNA expression.

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References:
Peterson, C.L. 2002. Mol. Cell 9, 921.
Remiszewski, S.W. 2002. Curr. Opin. Drug Discov. Devel. 5, 487.
Suenaga, M., et al. 2002. Int. J. Cancer 97, 621.
Marks, P.A., et al. 2001. Curr. Opin. Oncol. 13, 477.
Marks, P.A., et al. 2001. Nat. Rev. Cancer 1, 194.
Yoshida, M., et al. 2001. Cancer Chemother. Pharmacol. 48 ( Suppl 1):S20.
Jung. M., et al. 2001. Curr. Med. Chem. 8, 1505.
Pandolfi,P.P., 2001. Cancer Chemother. Pharmacol. 48 (Suppl 1), S17.
Munster, P.N., et al. 2001. Cancer Res. 61, 8492.

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Antibodies to Histones & Histone Deacetylases

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Assays

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Inhibitors

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Proteins/Enzymes

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