Open AccessCellular conditioning with trichostatin A enhances the anti‐stress response through up‐regulation of HDAC4 and down‐regulation of the IGF/Akt pathway
Author(s) -
Chu Fei,
Chou Pauline,
Mirkin Bernard L.,
Mousa Shaker A.,
Rebbaa Abdelhadi
Publication year - 2008
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2008.00403.x
Subject(s) - trichostatin a , biology , gene knockdown , chromatin , cellular stress response , microbiology and biotechnology , protein kinase b , hdac4 , histone , dna damage , histone deacetylase , pi3k/akt/mtor pathway , chromatin remodeling , dna repair , signal transduction , cancer research , cell culture , genetics , dna , gene , fight or flight response
Summary Evidence is accumulating that chromatin plays a major role in the control of cellular response to stress. This is best illustrated by the recent findings that chromatin‐modifying factors of class III histone deacetylases (sirtuins) are capable of protecting cells from oxidative and genotoxic stress. In particular, Sirt1 has been shown to mimic the action of caloric restriction for the prevention of aging‐associated diseases. In the present study, we have investigated the potential role of class I and II histone deacetylases (HDACs) in cellular protection against various stresses, including those caused by nutrient deprivation. For this, we utilized a cellular model in which expression of class I and II HDACs was altered as a result of cellular adaptation to trichostatin A (TSA), a selective inhibitor of these deacetylases. Our results indicated that TSA‐resistant cells also developed resistance to H 2 O 2 , DNA‐damaging agents, and to nutrient deprivation. Interestingly, the insulin signaling pathway mediated by Akt was inhibited in the TSA‐resistant cells, mirroring the effect of glucose deprivation on this pathway. Since expression of HDAC4 was consistently enhanced in the TSA‐resistant cell lines, we suggest that this enzyme may contribute to their anti‐stress response. In agreement with this, siRNA‐mediated knockdown of HDAC4 in stress‐resistant cells enhanced their sensitivity to the DNA‐damaging drug doxorubicin and also to glucose deprivation. Akt phosphorylation was also up‐regulated in response to HDC4 knockdown. Together, these findings suggest that cellular conditioning with TSA may represent a useful approach to mimic the effects of caloric restriction.