Class IIb contain unique domains unlike the other classes

Class IIb contain unique domains unlike the other classes. base, while Tyr306 and His142 stabilize the oxyanion intermediate. Metal-dependent HDACs share common sequence motifs (Figure 3), including a deacetylase domain that is comprised of an arginase-deacetylase fold consisting of a multistrand when compared to class I enzymes. Finally, HDAC11, the only class IV metal-dependent deacetylase, possesses characteristics from both class I and II enzymes and is expressed in higher abundance in specific tissues such as brain, heart, and kidney.22 Open in a separate window Figure 3 Schematic comparison of the metal-dependent deacetylases. All isozymes possess a common deacetylase domain. Class I isozymes are highly conserved and small. Class IIa isozymes have specific MEF2-binding domains in addition to their conserved deacetylase domains. Class IIb contain unique domains AS8351 unlike the other classes. Only the deacetylase domain has been identified in class IV. Crystal structures have been solved for HDAC1 (PDB: 4BKX), HDAC2 (PDB: 3MAX), HDAC3 (PDB: 4A69), HDAC4 (PDB: 2VQM), HDAC6 (PDB: 3PHD), HDAC7 (PDB: 3C0Y; catalytic domain only), HDAC8 (PDB: 2V5W), and AS8351 HDAC9 (PDB: 1TQE). The isozymes lacking crystal structures are HDAC5, HDAC10, and HDAC11. One of the most prevalent questions in the HDAC field is the substrate selectivity of each isozyme. There are over 3600 validated mammalian acetylation sites5 and 18 deacetylase isozymes. Thus, defining the substrate pool for each isozyme is essential for understanding Mouse monoclonal to p53 the biological functions of acetylation. Additionally, the substrate specificity of HDACs might be regulated by oxidative stress, proteinCprotein interactions, and other PTMs. Elucidating HDAC substrate specificity and regulation will provide insight into the function and control of acetylation sites in proteins. Much research in the field has focused on class I HDACs; thus, only the most recent work on that class is cited in this review. Classes IIa, IIb, and IV have fewer published studies, and the literature is therefore covered more extensively. In this review, we highlight functions of metal-dependent deacetylases with regard to epigenetic regulation and homeostasis and how these modifications play a role in cell proliferation and growth in various cancers, in addition to other, as of now, unknown roles. CLASS I HDACS The class I HDAC subfamily is disregulated in cancers and is the best studied subfamily of the metal-dependent deacetylases. Overexpression of this subclass has been observed in a variety of cancers such AS8351 as gastric,24 breast,9 prostate,8 and colon,10 as well as T-cell25 and Hodgkins lymphoma.26 Class I proteinCprotein interactions are currently the most well understood (Table 1). Table 1 Summary of Cancer and Disease Related HDACCProtein Interactions and Associated Phenotypes for Class I (1, 2, 3, and 8) and Class IV (11) HDACs siRNA leads to an increase in p53 DNA binding activity, Bax activation, and Bcl2 suppression36 These changes in Bax activation and Bcl2 suppression are consistent with suppressed expression of cyclin E2, cyclin D1, and CDK2, blocking cell proliferation and inducing apoptosis.37 Truncations of HDAC2 have been detected in a large number of cancers38 and knockouts of AS8351 both HDAC1 and HDAC2 prompt TRAIL-induced apoptosis in chronic lymphocytic leukemia (CLL), indicating a possible level of cooperativity between these two isozymes.39 Recent studies have also shown that both HDAC2 silencing and inhibition induce regression of fibrotic formation in Peyronies disease models.40,41 Using mutant fibroblasts that are.