HDACs in cancer and metabolism - Specific functions and selective targeting of histone/lysine deacetylases (HDACs) in cancer and metabolic disorders

Lysine deacetylases had initially been identified as the enzymes that remove acetylgroups from the ε-aminogroups of lysine residues in the N-terminal part of histone proteins. This activity had coined their name but by now it is obvious that hundreds of proteins can be acetylated at various lysine residues. It is highly likely that these acetyl groups can not only be added to target proteins by specific acetyltransferases but also be removed in a controlled fashion by lysine/histone deacetylases (KDACs / HDACs).

There are by now 18 human lysine deactylases known. The challenges are to understand which KDACs are relevant for which acetylated substrate protein and which key roles are served in pathophysiological processes by an individual KDAC. KDAC inhibitors such as Vorinostat, valproic acid, Romidepsin and Panobinostat targeting a relatively broad spectrum of KDACs have been successfully used to treat certain (rare) forms of cancer indicating that KDACs are a promising target for pharmaceutical intervention. On the other hand knock-out studies in mice indicate that each HDAC appears to serve quite specific roles in a wide variety of (patho-)physiological processes including e.g. proper embryonic development, control of cardiac size and hypertrophy, body size, bone ossification and cancer development. With a few exceptions the potential of isoenzyme-selective inhibitors has so fa only poorly been explored. We aim to understand and to target specific differences between two very closely related KDACs, i.e. HDAC1 and HDAC2. Our research is based on the key observations that HDAC2 deficient mice show a reduced body weight without obvious signs of additional disorders and that HDAC2 is overexpressed in most cases of human colorectal cancer where disease progression is associated with increasing HDAC2 expression.