Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1.
| Title: | Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1. |
|---|---|
| Authors: | Gendarme M; BioMed X Innovation Center, 69120 Heidelberg, Germany.; Baumann J; BioMed X Innovation Center, 69120 Heidelberg, Germany.; Ignashkova TI; BioMed X Innovation Center, 69120 Heidelberg, Germany.; Lindemann RK; Translational Innovation Platform Oncology, Merck Biopharma, Merck KGaA, 64293 Darmstadt, Germany.; Reiling JH; BioMed X Innovation Center, 69120 Heidelberg, Germany reiling@bio.mx. |
| Source: | Molecular biology of the cell [Mol Biol Cell] 2017 Dec 15; Vol. 28 (26), pp. 3756-3772. Date of Electronic Publication: 2017 Oct 26. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Society for Cell Biology Country of Publication: United States NLM ID: 9201390 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1939-4586 (Electronic) Linking ISSN: 10591524 NLM ISO Abbreviation: Mol Biol Cell Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Bethesda, MD : American Society for Cell Biology, c1992- |
| MeSH Terms: | Azepines/*pharmacology ; Drug Evaluation, Preclinical/*methods ; Histone Deacetylase 1/*metabolism ; Histone Deacetylase Inhibitors/*pharmacology ; Triazoles/*pharmacology; Apoptosis/drug effects ; Gene Expression Profiling/methods ; Golgi Apparatus/drug effects ; Histone Deacetylase 1/genetics ; Histone Deacetylases/metabolism ; Histones/metabolism ; Cell Line, Tumor ; Drug Synergism ; Humans |
| Abstract: | The Golgi apparatus is increasingly recognized as a major hub for cellular signaling and is involved in numerous pathologies, including neurodegenerative diseases and cancer. The study of Golgi stress-induced signaling pathways relies on the selectivity of the available tool compounds of which currently only a few are known. To discover novel Golgi-fragmenting agents, transcriptomic profiles of cells treated with brefeldin A, golgicide A, or monensin were generated and compared with a database of gene expression profiles from cells treated with other bioactive small molecules. In parallel, a phenotypic screen was performed for compounds that alter normal Golgi structure. Histone deacetylase (HDAC) inhibitors and DNA-damaging agents were identified as novel Golgi disruptors. Further analysis identified HDAC1/HDAC9 as well as BRD8 and DNA-PK as important regulators of Golgi breakdown mediated by HDAC inhibition. We provide evidence that combinatorial HDACi/(+)-JQ1 treatment spurs synergistic Golgi dispersal in several cancer cell lines, pinpointing a possible link between drug-induced toxicity and Golgi morphology alterations.; (© 2017 Gendarme et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).) |
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| Substance Nomenclature: | 0 ((+)-JQ1 compound); 0 (Azepines); 0 (Histone Deacetylase Inhibitors); 0 (Histones); 0 (Triazoles); EC 3.5.1.98 (HDAC1 protein, human); EC 3.5.1.98 (Histone Deacetylase 1); EC 3.5.1.98 (Histone Deacetylases) |
| Entry Date(s): | Date Created: 20171028 Date Completed: 20180123 Latest Revision: 20231112 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5739293 |
| DOI: | 10.1091/mbc.E17-03-0176 |
| PMID: | 29074567 |
| Database: | MEDLINE |
Journal Article