Acetylation Site Specificities of Lysine Deacetylase Inhibitors in Human Cells

Nat Biotechnol. 2015 Apr;33(4):415-23. doi: 10.1038/nbt.3130. Epub 2015 Mar 9.

Abstract

Lysine deacetylases inhibitors (KDACIs) are used in basic research, and many are being investigated in clinical trials for treatment of cancer and other diseases. However, their specificities in cells are incompletely characterized. Here we used quantitative mass spectrometry (MS) to obtain acetylation signatures for 19 different KDACIs, covering all 18 human lysine deacetylases. Most KDACIs increased acetylation of a small, specific subset of the acetylome, including sites on histones and other chromatin-associated proteins. Inhibitor treatment combined with genetic deletion showed that the effects of the pan-sirtuin inhibitor nicotinamide are primarily mediated by SIRT1 inhibition. Furthermore, we confirmed that the effects of tubacin and bufexamac on cytoplasmic proteins result from inhibition of HDAC6. Bufexamac also triggered an HDAC6-independent, hypoxia-like response by stabilizing HIF1-α, providing a possible mechanistic explanation of its adverse, pro-inflammatory effects. Our results offer a systems view of KDACI specificities, providing a framework for studying function of acetylation and deacetylases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Binding Sites
  • Cells, Cultured
  • Enzyme Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylases / chemistry*
  • Humans
  • Mass Spectrometry / methods*
  • Molecular Sequence Data
  • Peptide Mapping / methods*
  • Protein Binding
  • Protein Interaction Mapping / methods*

Substances

  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases