Experimental Approaches Toward Histone Acetyltransferase Inhibitors as Therapeutics

Dekker, F., 12-Jul-2016, Medical Epigenetics : Translational Epigenetics Series. Tollefsbol, T. (ed.). Academic Press, p. 685-704 20 p. Chapter 36

Research output: Chapter in Book/Report/Conference proceedingChapterAcademic

This chapter comprises the most recent developments with respect to the role of human histone acetyltransferases (HATs) in diseases and the potential therapeutic applications of HAT inhibitors. HATs form a diverse group of mainly nuclear enzymes that play an important role in the acetylation of lysine residues of histone- and nonhistone proteins. Acetylations of histone lysine residues are part of the histone code and contribute to the epigenetic regulation of gene transcription. Acetylation of nonhistone proteins such as transcription factors, nuclear receptors, and other enzymes, influences activity of these targets and links HAT activity to many different signal transduction cascades. Apart from their enzymatic activity HATs have also been described to play a role in protein–protein interactions in protein complexes. These diverse protein complexes determine substrate specificity and expand the range of targets.

Both the enzymatic activity and the structural role of HATs have been associated with several different diseases like cancer, inflammatory diseases, viral infections, and neuronal disorders. Although the development of therapeutics targeting HATs is still in a very early stage, significant efforts have been made to develop small molecule inhibitors of HAT activity. Inhibitors have been developed that are selective between HAT families. However, selectivity seems difficult to achieve due to the conserved acetyl coenzyme A binding site among the respective HAT families. An alternative strategy is development of allosteric inhibitors, because they have the potential to be selective between subtypes of the same family. HATs interact with many proteins, modulating their activity where sometimes acetylation activity is not even required, for example, through bromodomains or other protein interaction domains. Inhibition of these protein–protein interactions is a promising way of targeting specific HAT pathways.

Knowledge about HATs, HAT subtypes, and the correlation with histone- and nonhistone acetyltransferase is too fragmented to predict the effect of HAT inhibitors in disease state as yet. However, the current research on HAT inhibitors shows promising results for these important epigenetic enzymes to become drug targets for therapeutics against disease.
Original languageEnglish
Title of host publicationMedical Epigenetics
Subtitle of host publicationTranslational Epigenetics Series
EditorsTrygve Tollefsbol
PublisherAcademic Press
Number of pages20
ISBN (Electronic)9780128032404
ISBN (Print)978-0-12-803239-8
Publication statusPublished - 12-Jul-2016

ID: 38065786