highly regulated through post-translational modifications that control their activity, subcellular localization, or stability. The catalytic activity of Class I HDACs is regulated by phosphorylation by casein kinase II for HDACs 1–3 [42], and by PKA for HDAC8 [43, 44]. Class II HDACs respond to numerous environmental stimuli, from neural signaling to DNA damage. With neural signaling, for example, Ca2+ influx after depolarization results in activation of CaMKII, which in turns phosphorylates the class II HDACs HDAC4 and HDAC5 [45]. Phosphorylated HDAC4/5 recruit 14-3-3 proteins, which facilitate their nuclear export and reduce their activity in the nucleus [46]. Little is known about cytoplasmic functions of Class II HDACs with an exception of HDAC6, which is exclusively cytoplasmic and involved in deacetylating tubulin and shuttling misfolded proteins to the proteasome [47, 48]. Since Class III HDACs require NAD+ as a cofactor, their activity is traditionally thought to be dependent on the metabolic state of the cell (e.g. NAD+/NADH ratio). However, a recent study identified DBC1 (deleted in breast cancer 1) as a potent inhibitor of SIRT1 activity [49, 50], suggesting other upstream regulatory mechanisms also exist.
