Acetylation site specificities of lysine deacetylase inhibitors in human cells

Nature Biotechnology
Christian SchölzChunaram Choudhary

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.

References

May 10, 2000·Current Opinion in Cell Biology·W L CheungC D Allis
Jun 6, 2000·Microbiology and Molecular Biology Reviews : MMBR·D E Sterner, S L Berger
Sep 26, 2002·The Journal of Biological Chemistry·Kevin J BittermanDavid A Sinclair
Dec 17, 2002·Molecular and Cellular Biology·Michael W McBurneyMadeleine Lemieux
Apr 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Stephen J HaggartyStuart L Schreiber
Jan 28, 2006·Cell·Raul MostoslavskyFrederick W Alt
May 2, 2006·Genes & Development·Alejandro VaqueroDanny Reinberg
May 30, 2006·Molecular Cancer Therapeutics·Joseph J BuggyStacie A Dalrymple
Sep 7, 2006·Nature Reviews. Drug Discovery·Jessica E BoldenRicky W Johnstone
Jan 18, 2007·Proceedings of the National Academy of Sciences of the United States of America·Cleo M Salisbury, Benjamin F Cravatt
Jul 24, 2007·Molecular Cell·Xiaohong ZhangEdward Seto
Sep 25, 2007·Cell·Hongying YangDavid A Sinclair
Oct 20, 2007·Nature Protocols·Melissa S ClineGary D Bader
Oct 24, 2007·Molecular Cancer Research : MCR·Milos DokmanovicPaul A Marks
Jan 9, 2008·Molecular and Cellular Biology·Yu ZhangPatrick Matthias
Feb 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Brooke M EmerlingNavdeep S Chandel
May 2, 2008·Molecular & Cellular Proteomics : MCP·Leonie F WaandersMatthias Mann
May 13, 2008·Trends in Cell Biology·Agustín Valenzuela-FernándezFrancisco Sánchez-Madrid
Jul 26, 2008·Science·Tom Rolef Ben-ShaharFrank Uhlmann
Jul 26, 2008·Science·Elçin UnalDouglas E Koshland
Aug 30, 2008·Molecular Cell·Xiang-Jiao Yang, Edward Seto
Oct 2, 2008·Nature Reviews. Drug Discovery·Aleksey G Kazantsev, Leslie M Thompson
Apr 22, 2009·Proceedings of the National Academy of Sciences of the United States of America·Rusty L MontgomeryEric N Olson
Jul 31, 2009·Nature·Toren FinkelRaul Mostoslavsky
Feb 6, 2010·Journal of Hematology & Oncology·Jiahuai TanDelong Liu
Feb 9, 2010·Nature Chemical Biology·James E BradnerRalph Mazitschek
Feb 20, 2010·Science·Shimin ZhaoKun-Liang Guan
Aug 7, 2010·Expert Opinion on Investigational Drugs·Paul A Marks
Nov 4, 2010·Nucleic Acids Research·Damian SzklarczykChristian von Mering
Jan 25, 2011·Nature Biotechnology·Marcus BantscheffGerard Drewes
Feb 18, 2011·The New England Journal of Medicine·Holger K Eltzschig, Peter Carmeliet
Mar 12, 2011·Contact Dermatitis·Wolfgang Uter, Axel Schnuch
Mar 26, 2011·Journal of Aging Research·Gregory R Wagner, R Mark Payne
Jun 7, 2011·Molecular & Cellular Proteomics : MCP·Annette MichalskiStevan Horning
Jul 12, 2011·Critical Reviews in Immunology·Aleksander M GrabiecKris A Reedquist
Sep 29, 2011·The Journal of Dermatology·Hidetsugu FukudaHideki Mukai

❮ Previous
Next ❯

Citations

Sep 25, 2015·Protein Science : a Publication of the Protein Society·Tasha B Toro, Terry J Watt
Jan 30, 2016·Trends in Biochemical Sciences·Josue BaezaJohn M Denu
Nov 4, 2015·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Margarida D Amaral, William E Balch
Dec 25, 2015·Journal of Medicinal Chemistry·Roman P SimonManfred Jung
Oct 27, 2015·Trends in Endocrinology and Metabolism : TEM·Sean J HumphreyMatthias Mann
Jul 15, 2015·Biochimica Et Biophysica Acta·Luana Naia, A Cristina Rego
Nov 26, 2015·Epigenomics·Roberta NoberiniTiziana Bonaldi
Apr 12, 2016·Frontiers in Plant Science·Gaoyuan Song, Justin W Walley
Apr 18, 2016·Biochimica Et Biophysica Acta·Anna KazanetsMichael Witcher
May 28, 2015·Trends in Pharmacological Sciences·Alokta ChakrabartiManfred Jung
May 26, 2016·Nature Communications·Hani AlrefaiEdgar Serfling
Jun 11, 2016·Trends in Biochemical Sciences·Shahaf PelegAxel Imhof
Jul 3, 2016·Current Opinion in Chemical Biology·Niek Gj LeusFrank J Dekker
Jul 28, 2016·Nature Chemical Biology·Yasuyuki MiyakePatrick Matthias
Aug 31, 2016·Future Medicinal Chemistry·Alokta ChakrabartiManfred Jung
Oct 25, 2016·Nature Reviews. Cancer·Adam KinnairdEvangelos D Michelakis
Oct 23, 2016·Journal of Molecular Biology·Calley L HirschSharon Y R Dent
Oct 25, 2016·Journal of Proteomics·Jeovanis GilSergio Encarnación-Guevara
Nov 2, 2016·Analytical Chemistry·Keyun WangHanfa Zou
Dec 8, 2016·Nature Reviews. Molecular Cell Biology·Benjamin R SabariYingming Zhao
Dec 16, 2016·ACS Chemical Biology·Dhanusha A Nalawansha, Mary Kay H Pflum
Nov 11, 2016·PLoS Pathogens·Karl KuchlerNeeraj Chauhan
Feb 10, 2017·Cell Death & Disease·Hongfeng YuanShou-Jiang Gao
Jan 20, 2017·Epigenomics·Chiara AngiolilliKris A Reedquist
Apr 11, 2017·Cell Chemical Biology·Dhanusha A NalawanshaMary Kay H Pflum
Dec 4, 2016·Molecular & Cellular Proteomics : MCP·Michael H TathamRonald T Hay
Jul 7, 2017·Immunity, Inflammation and Disease·Felix LasitschkaJutta Schröder-Braunstein
Jun 20, 2017·ACS Chemical Biology·Jonathan IaconelliRakesh Karmacharya
Jan 30, 2016·Organic & Biomolecular Chemistry·Rob De VreeseMatthias D'hooghe
Nov 1, 2018·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Thangavel VaijayanthiHiroshi Sugiyama
Nov 30, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Zsofia KutilCyril Barinka
Jun 15, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kwi-Hoon JangNam-On Ku
Oct 25, 2017·Molecular Systems Biology·Markus HartlIris Finkemeier

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Cellular Oncology : the Official Journal of the International Society for Cellular Oncology
Madeleine S Q KortenhorstShabana Shabbeer
© 2022 Meta ULC. All rights reserved