A novel histone deacetylase inhibitor identified by high-throughput transcriptional screening of a compound library.
Libraries of compounds are increasingly becoming commercially available for the use of individual academic laboratories. A high-throughput system based on a stably integrated transcriptional reporter was used to screen a library of random compounds to identify agents that conferred robust augmentation of a signal transduction pathway. A novel histone deacetylase (HDAC) inhibitor, termed scriptaid, conferred the greatest effect, a 12- to 18-fold augmentation. This facilitation of transcriptional events was generally applicable to exogenous gene constructs, including viral and cellular promoters, different cell lines and reporter genes, and stably integrated and transiently introduced sequences. Scriptaid did not interfere with a further induction provided by stimulation of the cognate signal transduction pathway (transforming growth factor beta/Smad4), which implied the functional independence of ligand-stimulated transcriptional activation and histone acetylation states in this system. Additional insights into this and other signal transduction systems are likely to be afforded through the application of compound screening technologies.
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Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Sohn
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Ryu
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Kern
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D002470:Cell Survival / Q000187:drug effects; D002625:Chemistry, Organic; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D006898:Hydroxylamines / Q000737:chemistry / Q000494:pharmacology*; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D055601:Organic Chemistry Phenomena; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D006898:Hydroxylamines; D011804:Quinolines; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C410733:scriptaid; C012589:trichostatin A; D008156:Luciferases