Chromatin modifications such as acetylation, methylation, phosphorylation, ubiquitination, and sumoylation of histones play an important role in the regulation of transcription (1-5). Together with DNA methylation, these modifications are part of a broad and multifaceted strategy whereby eukaryotes regulate gene expression at the epigenetic level (6 -8).Acetylation of histones is tightly controlled by the activity of histone acetyltransferases and histone deacetylases (HDACs) 2 (9, 10). Histone deacetylation may repress transcription by different mechanisms. On the one hand, this process increases the charge density on the N termini of the core histones thereby strengthening histone tail-DNA interactions and blocking access of the transcriptional machinery to the DNA template. In addition, histone modifications are specifically recognized by chromatin-interacting proteins thus favoring the formation of higher order chromatin structures (heterochromatin).There is ample evidence that aberrations in the epigenetic regulation of gene expression at the levels of DNA methylation and histone acetylation or histone methylation are an important component in the process of malignant transformation of human cells (11). A number of histone acetyltransferase mutations were identified in cancer, and HDACs were found to be overexpressed or aberrantly recruited in several human malignancies (12). Small molecule HDAC inhibitors induce cell cycle arrest, differentiation, and apoptosis in cancer cells with a significant window over normal cells, and some molecules have already entered clinical trials and show promising results (13).Higher organisms have evolved a considerable complexity in the histone deacetylase family; thus, in mammals, 17 different HDAC subtypes were identified, which were grouped into three classes according to their sequence homologies with the yeast proteins Rpd3 (class I), HDA1 (class II), and Sir (class III) (14 -16). Class I and class II proteins are evolutionarily related and share a common enzymatic mechanism, the Zn-catalyzed hydrolysis of the acetyl-lysine amide bond. The HDAC inhibitors that are presently in clinical trials are rather nonselective and are thought to inhibit most or many of the class I and II proteins. Class III proteins are evolutionarily unrelated to class I or class II and catalyze the transfer of the acetyl group onto the sugar moiety of NAD (16
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