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

Molecular Biology of the Cell
Mathieu GendarmeJan H Reiling

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.

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Citations

Nov 30, 2018·Cell Structure and Function·Kanae SasakiHiderou Yoshida
Nov 28, 2018·Communications Biology·Hamed AlborziniaJan H Reiling
Feb 16, 2019·Nature Reviews. Urology·Sina JostesHubert Schorle
Jul 26, 2019·FEBS Letters·Kanae Sasaki, Hiderou Yoshida
Sep 4, 2020·Journal of Thrombosis and Haemostasis : JTH·Francesco FerraroDaniel F Cutler

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
acetylation
histone acetylation
transmission electron microscopy
glycosylation
fluorescence recovery after photobleaching
immunoprecipitation
nucleotide exchange
gene knockdown
genetic knockdown
transfections

Software Mentioned

Olympus ScanR
Connectivity Map ( CMap )
KNIME Analytics Platform
Image
Studio

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