title: Cellular conditioning with trichostatin A enhances the anti-stress response through up-regulation of HDAC4 and down-regulation of the IGF/Akt pathway.
abstract: 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.
authors.affiliation: Children's Memorial Research Center, Children's Memorial Hospital, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicargo, IL, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Chu
authors.forename: Pauline
authors.initials: P
authors.lastname: Chou
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Mirkin
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Rebbaa
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013002:Somatomedins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D013002:Somatomedins; C012589:trichostatin A; D051057:Proto-Oncogene Proteins c-akt; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D005947:Glucose