103 Epigenomics (2015) 7(1), 103–118 ISSN 1750-1911 part of Review 10.2217/EPI.14.69 © 2015 Future Medicine Ltd Histone deacetylase (HDAC)6 is a member of the class IIb HDAC family. This enzyme is zinc-dependent and mainly localized in the cytoplasm. HDAC6 is a unique isoenzyme with two functional catalytic domains and speciic physiological roles. Indeed, HDAC6 deacetylates various substrates including α-tubulin and HSP90α, and is involved in protein traficking and degradation, cell shape and migration. Consequently, deregulation of HDAC6 activity was associated to a variety of diseases including cancer, neurodegenerative diseases and pathological autoimmune response. Therefore, HDAC6 represents an interesting potential therapeutic target. In this review, we discuss structural features of this histone deacetylase, regulation of its expression and activity, biological functions, implication in human disease initiation and progression. Finally will describe novel and selective HDAC6 inhibitors. Keywords:฀ autoimmune฀response฀•฀cancer฀•฀epigenetics฀•฀HDAC6฀•฀HDAC6฀inhibitor฀ •฀histone฀deacetylase฀•฀neurodegenerative฀disease Acetylation of the ε nitrogen of lysine resi- dues is catalyzed by histone acetyltransferases (HATs). Deacetylation of both nuclear pro- teins (including histones) and cytoplasmic proteins is catalyzed by histone deacetylases (HDACs). In mammals, HATs are classified into two groups according to their cellular localiza- tion: group A is primarily nuclear, whereas group B is essentially cytoplasmic. A clas- sification system using their sequence simi- larities is compromised by the lack of simi- larity between these enzymes. However, selected enzymes are classified according to their sequence similarity and function into the following families: GNAT (gen- eral control [GC]N5 related N-acetyl- transferase), p300/CBP (cAMP response element-binding protein [CREB]-binding protein), MYST (MOZ, Ybf2/Sas3, SAS2 and TIP60), TAFII250 (TBP [TATA box binding protein]-associated factor 250 kDa) and steroid receptor cofactor (SRC) (for review, see [1]). All HAT enzymes use acetyl-coenzyme A as a cofactor. There are 18 mammalian HDACs subdi- vided into four classes based on their sequence identity and catalytic activity (Figure 1) . Indeed, classes I, II and IV are enzymes with a zinc ion at the bottom of their catalytic pocket essential for the deacetylation reac- tion; class III enzymes do not possess this ion, but their activity depends on the cofactor nicotinamide adenine dinucleotide (NAD + ). Class I includes HDAC1, 2, 3 and 8, which are located mainly in the nucleus due to the presence of a nuclear localization signal (NLS). Interestingly, HDAC3 possesses also a nuclear export signal (NES) in the catalytic domain. Class II is divided into two sub- classes: subclass IIa including HDAC4, 5, 7 and 9 and subclass IIb consisting of HDAC6 and 10. Class II isoenzymes possess a NLS as well as a NES except HDAC9 (NLS only) and HDAC10 (NES only). Class IV corre- sponds to HDAC11. Class III, also known as sirtuins by analogy with yeast silent informa- tion regulator 2 (SIR2), contains seven mem- bers, SIRT1 to 7; some members contain NES and/or NLS (for review, see [2]). Histone deacetylase 6 in health and disease Carole Seidel 1 , Michael Schnekenburger 1 , Mario Dicato 1 & Marc Diederich* ,2 1 Laboratory฀of฀Molecular฀&฀Cellular฀ Biology฀of฀Cancer,฀Hôpital฀Kirchberg,฀ L-2540฀Luxembourg,฀Luxembourg 2 Department฀of฀Pharmacy,฀College฀of฀ Pharmacy,฀Seoul฀National฀University,฀ Building฀20,฀Room฀303,฀1฀Gwanak-ro,฀ Gwanak-gu,฀Seoul฀151–742,฀Korea *Author฀for฀correspondence:฀ Tel.:฀+82฀2฀880฀8919 marcdiederich@snu.ac.kr For reprint orders, please contact: reprints@futuremedicine.com