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Gcn5 Modulates the Cellular Response to Oxidative Stress and Histone Deacetylase Inhibition
Author(s) -
Gaupel AnnChristin,
Begley Thomas J.,
Tenniswood Martin
Publication year - 2015
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25153
Subject(s) - histone acetyltransferase , gene knockdown , histone deacetylase , oxidative stress , pcaf , histone deacetylase inhibitor , programmed cell death , biology , mutant , microbiology and biotechnology , trichostatin a , histone , cancer research , chemistry , apoptosis , biochemistry , gene
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. J. Cell. Biochem. 116: 1982–1992, 2015. © 2015 Wiley Periodicals, Inc.