Acetylation site specificities of lysine deacetylase inhibitors in human cells

Christian Schölz; Brian T. Weinert; Sebastian A. Wagner; Petra Beli; Yasuyuki Miyake; Yun Qi; Lars J. Jensen; Werner Streicher; Anna Rose McCarthy; Nicholas James Westwood; Sonya Lain; Jürgen Cox; Patrick Matthias; Matthias Mann; James E. Bradner; Chunaram Choudhary

doi:10.1038/nbt.3130

Acetylation site specificities of lysine deacetylase inhibitors in human cells

Christian Schölz, Brian T. Weinert, Sebastian A. Wagner, Petra Beli, Yasuyuki Miyake, Yun Qi, Lars J. Jensen, Werner Streicher, Anna Rose McCarthy, Nicholas James Westwood, Sonya Lain, Jürgen Cox, Patrick Matthias, Matthias Mann, James E. Bradner, Chunaram Choudhary

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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.

Original language	English
Journal	Nature Biotechnology
Early online date	9 Mar 2015
DOIs	https://doi.org/10.1038/nbt.3130
Publication status	Published - 2015

Keywords

Acetylation
Deacetylase inhibitor
SILAC
HDAC
KDAC
Mass spectrometry
Proteomics
Sirtuin
Nicotinamide
Tenovin-6
Bufexamac

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nbt.3130

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Copyright 2015 the Authors. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at http://doi.org/10.1038/nbt.3130
Accepted author manuscript, 466 KB

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@article{5d3afdc5779e48af8ada079f500d1966,

title = "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.",

keywords = "Acetylation, Deacetylase inhibitor, SILAC, HDAC, KDAC, Mass spectrometry, Proteomics, Sirtuin, Nicotinamide, Tenovin-6, Bufexamac",

author = "Christian Sch{\"o}lz and Weinert, {Brian T.} and Wagner, {Sebastian A.} and Petra Beli and Yasuyuki Miyake and Yun Qi and Jensen, {Lars J.} and Werner Streicher and McCarthy, {Anna Rose} and Westwood, {Nicholas James} and Sonya Lain and J{\"u}rgen Cox and Patrick Matthias and Matthias Mann and Bradner, {James E.} and Chunaram Choudhary",

note = "This work was supported by the Hallas M{\o}ller 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.",

year = "2015",

doi = "10.1038/nbt.3130",

language = "English",

journal = "Nature Biotechnology",

issn = "1087-0156",

publisher = "Nature publishing group",

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TY - JOUR

T1 - Acetylation site specificities of lysine deacetylase inhibitors in human cells

AU - Schölz, Christian

AU - Weinert, Brian T.

AU - Wagner, Sebastian A.

AU - Beli, Petra

AU - Miyake, Yasuyuki

AU - Qi, Yun

AU - Jensen, Lars J.

AU - Streicher, Werner

AU - McCarthy, Anna Rose

AU - Westwood, Nicholas James

AU - Lain, Sonya

AU - Cox, Jürgen

AU - Matthias, Patrick

AU - Mann, Matthias

AU - Bradner, James E.

AU - Choudhary, Chunaram

N1 - 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.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Acetylation

KW - Deacetylase inhibitor

KW - SILAC

KW - HDAC

KW - KDAC

KW - Mass spectrometry

KW - Proteomics

KW - Sirtuin

KW - Nicotinamide

KW - Tenovin-6

KW - Bufexamac

UR - http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3130.html#supplementary-information

U2 - 10.1038/nbt.3130

DO - 10.1038/nbt.3130

M3 - Article

SN - 1087-0156

JO - Nature Biotechnology

JF - Nature Biotechnology

ER -

Acetylation site specificities of lysine deacetylase inhibitors in human cells

Abstract

Keywords

UN SDGs

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