title: Gcn5 Modulates the Cellular Response to Oxidative Stress and Histone Deacetylase Inhibition.
abstract: To identify chemical genetic interactions underlying the mechanism of action of histone deacetylase inhibitors (HDACi) a yeast deletion library was screened for hypersensitive deletion mutants that confer increased sensitivity to the HDACi, CG-1521. The screen demonstrated that loss of GCN5 or deletion of components of the Gcn5 histone acetyltransferase (HAT) complex, SAGA, sensitizes yeast to CG-1521-induced cell death. Expression profiling after CG-1521 treatment reveals increased expression of genes involved in metabolism and oxidative stress response, and oxidative stress response mutants are hypersensitive to CG-1521 treatment. Accumulation of reactive oxygen species and increased cell death are enhanced in the gcn5Δ deletion mutant, and are abrogated by anti-oxidants, indicating a central role of oxidative stress in CG-1521-induced cell death. In human cell lines, siRNA mediated knockdown of GCN5 or PCAF, or chemical inhibition of GCN5 enzymatic activity, increases the sensitivity to CG-1521 and SAHA. These data suggest that the combination of HDAC and GCN5/PCAF inhibitors can be used for cancer treatment.
authors.affiliation: Department of Biomedical Sciences, School of Public Health, University at Albany, New York.|Cancer Research Center, University at Albany, New York.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Gaupel
authors.affiliation: Cancer Research Center, University at Albany, New York.|Nanobioscience Constellation, SUNY Polytechnic Institute, Colleges of Nanoscale Science and Engineering, Albany, New York.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Begley
authors.affiliation: Department of Biomedical Sciences, School of Public Health, University at Albany, New York.|Cancer Research Center, University at Albany, New York.
authors.forename: Martin
authors.initials: M
authors.lastname: Tenniswood
mesh_terms: D016923:Cell Death; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D015723:Gene Library; D019073:HT29 Cells; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000633:toxicity*; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C531199:7-phenyl-2,4,6-heptatrienoylhydroxamic acid; C507785:SAGA complex, S cerevisiae; C501392:GCN5 protein, S cerevisiae
keywords: GCN5; HISTONE ACETYL TRANSFERASE; HISTONE DEACETYLASE; MAMMALIAN; OXIDATIVE STRESS; YEAST