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Histone acetylases and deacetylases as promising therapeutic targets

Regulation of gene expression is mediated by several mechanisms such as DNA methylation, ATP-dependent chromatin remodeling, and post-translational modifications of histones. The latter mechanism includes dynamic acetylation and deacetylation of ε-amino groups of lysine residues present in the tail of the core histones. Histones are the predominant protein components of chromatin, which stabilize the nucleosome core. They are subjected to a variety of specific post-translational modifications. Reversible acetylation and deacetylation of nucleosomal histones are critical in the modulation of chromatin structure, chromatin function and in the regulation of gene expression. Enzymes responsible for the reversible acetylation/deacetylation processes are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively [i]. HATs act as transcriptional coactivators, and HDACs are a part of transcriptional corepressor complexes. Moreover, these enzymes also target non-histone protein substrates, including transcription factors, nuclear import factors, cytoskeleton, and chaperon proteins. They were first described almost 30 years ago [ii]. These enzymes have been identified in numerous biological systems, including multiple mammalian cell lines and tissues [iiia], fungi [3b] plants [iv] and yeasts [v]. In particular, they have been received much attention as promising therapeutic targets for the treatment of many solid and hematological cancers in addition to diabetes, arthritis, polyglutamine and Huntington’s diseases. It is now becoming clear that HDACs play critical role in controlling transcription, cell cycle, cell motility, DNA damage response and senescence by deacetylating histones and non-histone proteins.

It became evidently clear, that aberrant gene expression through epigenetic changes represents a major area for the study of cancer initiation and progression [vi]. Research data accumulated over two decades suggest that errors in the regulation of histone acetylation are associated with carcinogenesis, cancer progression as well as with other malignancies [vii]. Cancer is a complicated process involving genetic and epigenetic events, which result in neoplastic transformation. Numerous alterations of pathways involving HDACs were identified in tumor cells. In general, histone acetylation leads to chromatin remodeling and de-repression of molecular transcription mechanism. Mechanistically, interaction of the positively charged ε-amino groups of lysine residues of histone N-terminal tails with
the negatively charged phosphate backbone of DNA results in chromatin condensation, leading to transcription silencing possibly by disallowing access to the transcription mechanism
Publications
i Balakin Konstantin V; Ivanenkov Yan A; Kiselyov Alex S; Tkachenko Sergey E. Histone deacetylase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective. Anti-cancer agents in medicinal chemistry 2007;7(5):576-92.
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xiii Taylor, P.J.; Kenneth, H.F. Trends in Molecular Medicine, 2002, 8, 195.
xiv Hockely, E.; Woodman, B.; Ghazi-Noori, S.; Mahal, A.; Marsh, J.L.; Lewis, C.M.; Bates, G.P.; Marks, P.A.; Thompson, L.M.; Steffa, J.S.; Lowden, P.A.; Sathasivam, K.; Rosa, E.; Zhou, X.; Smith, D.L. Proc. Natl. Acad. Sci., 2003, 18, 2041.
xv Chung, Y.-L.; Lee, M.-Y.; Wang, A.-J.; Lin-Fen. Mol. Therapy, 2003, 8, 707.
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xix Finnin, M.S.; Donigian, J.R.; Cohen, A.; Richon, V.M.; Rifkind, R.A.; Marks, P.A.; Breslow, R.; Pavletich, N.P. Nature, 1999, 401, 188.
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xxx Bouchain, G.; Leit, S.; Frechette, S.; Khalil, E.A.; Lavoie, R.; Moradei, O.; Woo, S.H.; Fournel, M.; Yan. P.T.; Kalita, A.; Trachy-Bourget, M.C.; Beaulieu, C.; Li, Z.; Robert, M.F.; MacLeod, A.R.; Besterman, J.M.; Delorme, D. J. Med. Chem., 2003, 46, 820.
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