Acetylation site specificities of lysine deacetylase inhibitors in human cells
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.
Citation
Schölz , C , Weinert , B T , Wagner , S A , Beli , P , Miyake , Y , Qi , Y , Jensen , L J , Streicher , W , McCarthy , A R , Westwood , N J , Lain , S , Cox , J , Matthias , P , Mann , M , Bradner , J E & Choudhary , C 2015 , ' Acetylation site specificities of lysine deacetylase inhibitors in human cells ' , Nature Biotechnology . https://doi.org/10.1038/nbt.3130
Publication
Nature Biotechnology
Status
Peer reviewed
ISSN
1087-0156Type
Journal article
Description
This work was supported by the Hallas Møller Investigator grant from the Novo Nordisk Foundation to C.C. S.A.W. and P.B. were supported by individual postdoctoral grants from the Danish Research Council (FSS: 10-085134, FSS: 12-12610). C.C. is supported by the EMBO Young Investigator program. J.E.B. is supported by a grant from the Doris Duke Charitable Foundation.Collections
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