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

Acetylation site specificities of lysine deacetylase inhibitors in human cells.

Author information

1
Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Protein Science and Technology, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
5
Department of Disease Systems Biology, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
6
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
7
School of Chemistry and Biomedical Sciences Research Complex, EaStCHEM, University of St. Andrews, St. Andrews, Scotland, UK.
8
Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany.

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.

PMID:
25751058
DOI:
10.1038/nbt.3130
[Indexed for MEDLINE]

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