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Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma
M. Zrimšek, H. Kuchaříková, K. Draganić, P. Dobrovolná, V. Heiss Spornberger, L. Winkelmayer, MR. Hassler, G. Lochmanová, Z. Zdráhal, G. Egger
Language English Country Switzerland
Document type Journal Article
Grant support
I 4066
FWF Austrian Science Fund
19-29701L
Czech Science Foundation
LM2018140
e-Infrastruktura CZ
NLK
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PubMed
35954222
DOI
10.3390/cells11152380
Knihovny.cz E-resources
- MeSH
- Acetylation MeSH
- Lymphoma, Large-Cell, Anaplastic * drug therapy MeSH
- Chromatography, Liquid MeSH
- Histone Deacetylases * metabolism MeSH
- Histones metabolism MeSH
- Hydroxamic Acids pharmacology MeSH
- Mice MeSH
- Tandem Mass Spectrometry MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Histone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell cycle, cell death and differentiation and thus critically involved in tumorigenesis. Further, HDACs regulate T-cell development and HDAC inhibitors (HDACis) have been approved for clinical use in some T-cell malignancies. Still, the exact targets and mechanisms of HDAC inhibition in cancer are understudied. We isolated tumor cell lines from a transgenic mouse model of anaplastic large cell lymphoma (ALCL), a rare T-cell lymphoma, and abrogated HDAC activity by treatment with the HDACis Vorinostat and Entinostat or Cre-mediated deletion of Hdac1. Changes in overall protein expression as well as histone and protein acetylation were measured following Hdac1 deletion or pharmacological inhibition using label-free liquid chromatography mass spectrometry (LC-MS/MS). We found changes in overall protein abundance and increased acetylation of histones and non-histone proteins, many of which were newly discovered and associated with major metabolic and DNA damage pathways. For non-histone acetylation, we mapped a total of 1204 acetylated peptides corresponding to 603 proteins, including chromatin modifying proteins and transcription factors. Hyperacetylated proteins were involved in processes such as transcription, RNA metabolism and DNA damage repair (DDR). The DDR pathway was majorly affected by hyperacetylation following HDAC inhibition. This included acetylation of H2AX, PARP1 and previously unrecognized acetylation sites in TP53BP1. Our data provide a comprehensive view of the targets of HDAC inhibition in malignant T cells with general applicability and could have translational impact for the treatment of ALCL with HDACis alone or in combination therapies.
Central European Institute of Technology Masaryk University 625 00 Brno Czech Republic
Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria
Department of Pathology Medical University of Vienna 1090 Vienna Austria
Department of Urology Medical University of Vienna 1090 Vienna Austria
Ludwig Boltzmann Institute Applied Diagnostics 1090 Vienna Austria
References provided by Crossref.org
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