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Mol Biol Cell. 2017 Dec 15;28(26):3756-3772. doi: 10.1091/mbc.E17-03-0176. Epub 2017 Oct 26.

Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1.

Author information

1
BioMed X Innovation Center, 69120 Heidelberg, Germany.
2
Translational Innovation Platform Oncology, Merck Biopharma, Merck KGaA, 64293 Darmstadt, Germany.
3
BioMed X Innovation Center, 69120 Heidelberg, Germany reiling@bio.mx.

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.

PMID:
29074567
PMCID:
PMC5739293
DOI:
10.1091/mbc.E17-03-0176
[Indexed for MEDLINE]
Free PMC Article

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