Proteomics

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Unraveling Lysine Deacetylase Inhibitor Specificities for Endogenous Acetylation Sites

ABSTRACT: Lysine deacetylases (KDACs) are important regulators of biological processes. KDAC inhibitors (KDACIs) are important tools for basic research and attractive therapeutic candidates, yet their effects on in-vivo acetylation sites are poorly known. Here we obtained acetylation signatures for 19 different KDACIs that cover all known deacetylases. Most KDACIs targeting non-sirtuin deacetylases increased acetylation of a small, but specific, subset of the acetylome, and included sites on histone and other chromatin-associated proteins. Using a combination of genetic deletion and inhibitor treatment we found that the sirtuin inhibitor nicotinamide increased acetylation via SIRT1 inhibition, whereas tubacin and bufexamac affected cytoplasmic proteins through inhibition of HDAC6. Bufexamac additionally triggered an HDAC6-independent hypoxia-like response by stabilizing HIF1-α, providing a potential mechanistic basis for its adverse pro-inflammatory effects. Our results provide a systematic view of the scope and specificities of KDACIs for acetylation sites, and uncovered unexpected acetylation profiles for several of commonly used inhibitors.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Christian Schölz  

LAB HEAD: Chunaram Choudhary

PROVIDER: PXD001377 | Pride | 2015-02-16

REPOSITORIES: Pride

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Dataset's files

Source:
Action DRS
20101130_Velos2_PB_CHU_QSA_MV4-11-NA-24h-IP-AcK-oneshot-test_S01.raw Raw
20101209_Velos2_PB_SA_MV4-11_NA_ACKIP_OFFGEL_01.raw Raw
20101209_Velos2_PB_SA_MV4-11_NA_ACKIP_OFFGEL_02.raw Raw
20101209_Velos2_PB_SA_MV4-11_NA_ACKIP_OFFGEL_03.raw Raw
20101209_Velos2_PB_SA_MV4-11_NA_ACKIP_OFFGEL_04.raw Raw
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Publications

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  ...[more]