Journal
NATURE BIOTECHNOLOGY
Volume 33, Issue 4, Pages 415-U136Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3130
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Funding
- Novo Nordisk Foundation [NNF14CC0001]
- Danish Research Council [FSS: 10-085134, FSS: 12-12610]
- EMBO Young Investigator program
- Doris Duke Charitable Foundation
- Novo Nordisk Fonden [NNF15SA0018240, NNF14OC0008541] Funding Source: researchfish
- Novo Nordisk Foundation Center for Protein Research [PI Matthias Mann, PI Chunaram Choudhary] Funding Source: researchfish
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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-alpha, 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.
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