Gcn5 Modulates the Cellular Response to Oxidative Stress and Histone Deacetylase Inhibition.
JOURNAL OF CELLULAR BIOCHEMISTRY(2015)
摘要
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 gcn5 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. (c) 2015 Wiley Periodicals, Inc.
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关键词
HISTONE DEACETYLASE,GCN5,HISTONE ACETYL TRANSFERASE,OXIDATIVE STRESS,YEAST,MAMMALIAN
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