Title:Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease
Volume: 24
Issue: 37
Author(s): Andre Richters and Angela N. Koehler*
Affiliation:
- David H. Koch Institute for Integrative Cancer Research, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA,United States
Keywords:
Histone acetyltransferases, p300/CBP, PCAF, GCN5, Tip60, epigenetics, small molecule inhibitors,
cancer.
Abstract: Histone acetyltransferases (HATs) are epigenetic drivers that catalyze the acetyl
transfer from acetyl-CoA to lysines of both histone and non-histone substrates and thereby
induce transcription either by chromatin remodeling or direct transcription factor activation.
Histone deacetylases (HDACs) conduct the reverse reaction to counter HAT activity. Physiological
processes such as cell cycle progression or apoptosis require a thoroughly balanced
equilibrium of the interplay between acetylation and deacetylation processes to maintain or, if
required, alter the global acetylome status. Aberrant HAT activity has recently been demonstrated
to play a crucial role in the progression of various diseases such as prostate, lung, and
colon cancers as well as glioblastomas and neurodegenerative diseases. Recent investigations
have aimed for the identification of HAT modulators to further decipher the complexity of
acetyl transferase related signaling cascades and discover potential leads for drug design approaches.
HDACs have been extensively characterized and targeted by small molecules, including
four FDA-approved HDAC inhibitors; in contrast, HATs have not been active targets
for therapeutic development. This review will summarize the status of HAT associated diseases
and the arsenal of currently known and available HAT inhibitors with respect to their
discovery, further improvements, and current applications.
