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  Histone Deacetylase Inhibitors (HDACi) Cause the Selective Depletion of Bromodomain Containing Proteins (BCPs)

Mackmull, M.-T., Iskar, M., Parca, L., Singer, S., Bork, P., Ori, A., et al. (2015). Histone Deacetylase Inhibitors (HDACi) Cause the Selective Depletion of Bromodomain Containing Proteins (BCPs). Molecular and Cellular Proteomics, 14(5), 1350-1360. doi:10.1074/mcp.M114.042499.

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Mackmull, Marie-Therese1, Author
Iskar, Murat1, Author
Parca, Luca1, Author
Singer, Stephan1, Author
Bork, Peer1, Author
Ori, Alessandro1, Author
Beck, Martin2, Author           
Affiliations:
1External Organizations, ou_persistent22              
2European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, ou_persistent22              

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Free keywords: Acetylation, Butyric Acid, Carrier Proteins, CREB-Binding Protein, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Silencing, HeLa Cells, Histone Chaperones, Histone Deacetylase Inhibitors, Histone Deacetylases, Histones, Humans, Hydroxamic Acids, Nuclear Proteins, Protein Processing, Post-Translational, RNA, Small Interfering, Transcription Factors, Transcription, Genetic, Vorinostat
 Abstract: Histone deacetylases (HDACs) and acetyltransferases control the epigenetic regulation of gene expression through modification of histone marks. Histone deacetylase inhibitors (HDACi) are small molecules that interfere with histone tail modification, thus altering chromatin structure and epigenetically controlled pathways. They promote apoptosis in proliferating cells and are promising anticancer drugs. While some HDACi have already been approved for therapy and others are in different phases of clinical trials, the exact mechanism of action of this drug class remains elusive. Previous studies have shown that HDACis cause massive changes in chromatin structure but only moderate changes in gene expression. To what extent these changes manifest at the protein level has never been investigated on a proteome-wide scale. Here, we have studied HDACi-treated cells by large-scale mass spectrometry based proteomics. We show that HDACi treatment affects primarily the nuclear proteome and induces a selective decrease of bromodomain-containing proteins (BCPs), the main readers of acetylated histone marks. By combining time-resolved proteome and transcriptome profiling, we show that BCPs are affected at the protein level as early as 12 h after HDACi treatment and that their abundance is regulated by a combination of transcriptional and post-transcriptional mechanisms. Using gene silencing, we demonstrate that the decreased abundance of BCPs is sufficient to mediate important transcriptional changes induced by HDACi. Our data reveal a new aspect of the mechanism of action of HDACi that is mediated by an interplay between histone acetylation and the abundance of BCPs. Data are available via ProteomeXchange with identifier PXD001660 and NCBI Gene Expression Omnibus with identifier GSE64689.

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Language(s): eng - English
 Dates: 2014-07-152015-03-092015-05-01
 Publication Status: Issued
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1074/mcp.M114.042499
BibTex Citekey: mackmull_histone_2015
 Degree: -

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Title: Molecular and Cellular Proteomics
Source Genre: Journal
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Publ. Info: Bethesda, MD : American Society for Biochemistry and Molecular Biology
Pages: - Volume / Issue: 14 (5) Sequence Number: - Start / End Page: 1350 - 1360 Identifier: ISSN: 1535-9476
CoNE: https://pure.mpg.de/cone/journals/resource/111035577487002