ABSTRACT
Inhibitors as Anticancer Agents ................................................................ 170 9.5 Conclusion Remarks: The Potential of Sirtuins as Molecular Target for the
Intervention of Aging and Tumorigenesis ......................................................................... 170 References ..................................................................................................................................... 173
Eukaryotic gene expression is tightly controlled by chromatin remodeling through the modification of core histones. Acetylation is one of the most intensively studied modifications, which is highly regulated by two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs deliver acetyl groups to the lysine residues in the amino terminal tail of core histones, neutralize the positive charge, and result in the unwinding of chromatin. Acetylation provides docking sites for regulatory proteins to activate transcription. HDACs, on the other hand, induce transcriptional repression and gene silencing by catalyzing the removal of the acetyl groups from core histones. In humans, 18 HDACs have been identified, which are divided into 4 subclasses based on their homology to yeast proteins [1]. The class I HDACs, including 1, 2, 3, and 8, are ubiquitously expressed nuclear proteins homologous to the yeast RPD3. Class II HDACs (4, 5, 6, 7, 9, and 10) are homologous to yeast Hda1 and can be found in both the nucleus and the cytoplasm. HDAC11 is remotely similar to class I and II HDACs but the sequence identity is too weak to be placed in either class [2]. It is thus designated as the sole member of class IV. All members of class I, II, and IV HDACs are sensitive to the inhibition by trichostatin A (TSA).
