Histone Acetylase and Deacetylase Inhibitors
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. Acetylated histone proteins confer accessibility of the DNA template to the transcriptional machinery for expression. 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 uncontrolled cell proliferation. Histone deacetylases (HDAC), on the other hand, are chromatinremodeling factors that 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. In humans at least 16 different HDACs have been reported that are subdivided into Class I (HDAC 1, 2, 3, and 8); Class II (HDAC 4, 5, 6, 7, 9, and 10), and Class III (SIRT 1-7). Class I HDACs are widely expressed in tissues, and are primarily located in the nucleus. Class II HDACs are much larger in size and display limited tissue distribution. They can shuttle between the nucleus and cytoplasm. Class III HDACs consist of a large family of sirtuins (silent information regulators or SIR) that are evolutionarily distinct, with unique enzymatic mechanisms dependent on NAD+. Studies have shown that certain oncogenes repress transcription by recruitment of HDACs. This has led 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. HDAC inhibitors are also reported to induce the expression of pro-apoptotic Bak, down regulate the expression of anti-apoptotic Bcl-XL, and promote mitochondrial localization of Bax and Bak. They are also shown to increase the DNA-binding activities of AP1, CREB, and NF-kB transcription factors and are also reported to down-regulate telomerase activity via suppression of hTERT mRNA expression. The best-studied inhibitor of HDAC is Trichostatin A, a hydroxamic acid that complexes with zinc and mediates the acetamide cleavage at the catalytic site.
Mariadason, J.M. 2008. Epigenetics. 3, 28.
Bolden, J.E., et al. 2006. Nat. Rev. Drug Dis. 5, 769.
Acharya, M. R., et al. 2005. Mol. Pharmacol. 68, 917.
Mei, S. et al. 2004. Int. J. Oncol. 25, 1509.
Suenaga, M., et al. 2002. Int. J. Cancer 97, 621.
Marks, P.A., et al. 2001. Curr. Opin. Oncol. 13, 477.
Jung. M., et al. 2001. Curr. Med. Chem. 8, 1505.
Munster, P.N., et al. 2001. Cancer Res. 61, 8492.
Yoshida, M., et al. 2001. Cancer Chemother. Pharmacol. 48 (Suppl 1), S20.
Pandolfi, P.P., 2001. Cancer Chemother. Pharmacol. 48 (Suppl 1), S17