Acetylation site specificities of lysine deacetylase inhibitors in human cells

TY - JOUR

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

AU - Schölz, Christian

AU - Weinert, Brian Tate

AU - Wagner, Sebastian A

AU - Beli, Petra

AU - Miyake, Yasuyuki

AU - Qi, Jun

AU - Jensen, Lars J

AU - Streicher, Werner

AU - McCarthy, Anna R

AU - Westwood, Nicholas J

AU - Lain, Sonia

AU - Cox, Jürgen

AU - Matthias, Patrick

AU - Mann, Matthias

AU - Bradner, James E

AU - Choudhary, Chuna Ram

PY - 2015/4/1

Y1 - 2015/4/1

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.

U2 - 10.1038/nbt.3130

DO - 10.1038/nbt.3130

M3 - Journal article

C2 - 25751058

SN - 1087-0156

VL - 33

SP - 415

EP - 423

JO - Nature Biotechnology

JF - Nature Biotechnology

ER -