Acetylation site specificities of lysine deacetylase inhibitors in human cells

作者：Scholz Christian; Weinert Brian T; Wagner Sebastian A; Beli Petra; Miyake Yasuyuki; Qi Jun; Jensen Lars J; Streicher Werner; McCarthy Anna R; Westwood Nicholas J; Lain Sonia; Cox Juergen; Matthias Patrick; Mann Matthias; Bradner James E; Choudhary Chunaram^*

来源：Nature Biotechnology, 2015, 33(4): 415-U136.

DOI：10.1038/nbt.3130

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.

• 出版日期2015-4