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

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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.", "claims": [{"id": "claim-method", "statement": "Protein differential expression was evaluated using the limma package (29). Differences in protein abundances were statistically determined using the Student's t test moderated by the empirical Bayes method.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:25755299", "locator": "sections[13] \"Protein Identification by Mass Spectrometry\" paragraph 4", "quote": "Protein differential expression was evaluated using the limma package (29). Differences in protein abundances were statistically determined using the Student's t test moderated by the empirical Bayes method."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data are available via ProteomeXchange with identifier PXD001660 and NCBI Gene Expression Omnibus with identifier GSE64689.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:25755299", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Data are available via ProteomeXchange with identifier PXD001660 and NCBI Gene Expression Omnibus with identifier GSE64689."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Headline result: HDACi treatment primarily affects the nuclear proteome and selectively decreases bromodomain-containing proteins. Statistical method: differential protein expression was evaluated with limma, using Student's t test moderated by empirical Bayes. 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