Please cite this article in press as: M.. Ghizzoni, et al., Histone acetyltransferases are crucial regulators in NF-kB mediated inflammation, Drug Discov Today (2011), doi:10.1016/ j.drudis.2011.03.009 Drug Discovery Today  Volume 00, Number 00  April 2011 REVIEWS Histone acetyltransferases are crucial regulators in NF-kB mediated inflammation Massimo Ghizzoni 1 , Hidde J. Haisma 1 , Harm Maarsingh 2 and Frank J. Dekker 1 1 Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands 2 Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands Post-translational modifications of proteins, such as acetylation, are important regulatory events in eukaryotic cells. Reversible acetylations of histones and non-histone proteins regulate gene expression and protein activity. Acetylation levels of proteins are regulated by a dynamic equilibrium between acetylation by (histone) acetyltransferases and deacetylation by (histone) deacetylases. Alterations in this equilibrium can result in pathological states. Inflammation is a physiological response that, under certain conditions, turns into a disease. This review focuses on the crucial regulatory roles of protein acetylation in NF-kB-mediated inflammation and the potential applications of small-molecule inhibitors of acetylation for the treatment of inflammatory diseases. All cellular processes are regulated by a complex and dynamic network of signals and interactions that allows cells to respond to alteration in the cellular environment. This network is, among others, regulated by post-translational modifications such as acet- ylation, methylation phosphorylation and ubiquitination. These modifications alter protein–protein interactions, modulate enzyme activity and function as regulatory switches for many cellular processes. Histones are small proteins around which DNA is wrapped to form the basic packaging unit of DNA called the ‘nucleosome’. Post-translational modifications of histones modify their interactions with DNA and with other proteins, and change the chromatin structure to expose promoter regions for binding of transcription factors. Inflammation is a physiological response, triggered by physical, biological or chemical stimuli, which is necessary for cell survival. Under certain circumstances, however, the inflammatory response is inappropriate or excessive, which leads to pathological states. Abnormal and chronic inflammatory responses have been asso- ciated with various diseases including asthma, cancer, diabetes and neurodegenerative diseases. It has been demonstrated clearly that post-translational mod- ifications of proteins play a crucial part in regulating the intensity, the duration and the specificity of inflammatory responses. This review focuses on the role of histone and non-histone protein acetylations by histone acetyltransferases (HATs) in nuclear factor kB (NF-kB)-mediated inflammation. Furthermore, we discuss the inhibition of acetylation by small-molecule HAT inhibitors as a potential therapeutic approach to control inflammation. Protein acetylation Reversible acetylation of histones and other proteins is modulated by the activity of HATs and histone deacetylases (HDACs). These enzymes catalyze, respectively, the introduction or removal of acetyl groups from e-amino functionalities of specific lysine resi- dues. HATs are classified based on their cellular localization in nuclear HATs (type A) and cytoplasmatic HATs (type B) [1]. Several nuclear HATs have been identified, whereas only one cytoplas- matic HAT (HAT 1) has been described so far. HATs have been divided into five families based on their primary structure homol- ogy. The three families that have been studied extensively are: the GNAT (GCN5-related N-acetyltransferase) family, represented by GCN5 (general control nonderepressible 5) and PCAF (p300/CBP associated factor); the p300/CBP family, including p300 and CBP Reviews  POST SCREEN Corresponding author:. Dekker, F.J. (f.j.dekker@rug.nl) 1359-6446/06/$ - see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2011.03.009 www.drugdiscoverytoday.com 1