title: Comparative effects of histone deacetylase inhibitors on p53 target             gene expression, cell cycle and apoptosis in MCF-7 breast cancer cells.
abstract: Histone deacetylase inhibitors are currently being evaluated for their therapeutic             potential and have shown considerable promise as adjuvant therapies for a number             of cancers. This study compared the effects of 2 hydroxamic acid based inhibitors,             CG-1521 and SAHA, on gene expression, cell cycle and cell death in MCF-7 human             breast cancer cells. Both compounds show a dose- and time-dependent effect on             cell number (evaluated using crystal violet), however CG-1521 exerts its effects             significantly earlier than SAHA, and CG-1521 induces apoptosis (assessed by Apo-BrdU             staining and flow cytometry) more rapidly than SAHA. qPCR of cell cycle regulatory             and apoptotic genes shows that CG-1521 and SAHA modulate similar cohorts of p53-responsive             genes, however, the levels of induction and the timing of the induction differs             significantly between the 2 inhibitors. In particular SAHA downregulates cell             cycle-associated genes that modulate the G1/S transition (including cyclin D1             and cdc25a) and the G2/M transition [cyclin B1, Plk1, Stk6 (serine-threonine kinase             6, Aurora kinase A) and Kntc2] more significantly than CG-1521. In contrast, CG-1521             significantly induces the expression of several p53 target genes associated with             apoptosis including Bnip3/Bnip3L, p21/p21B and Gdf15. The differential levels             of gene induction provide molecular evidence of both cell cycle arrest and apoptosis,             and suggest a molecular mechanism that explains the difference in the biological             effects of the 2 histone deacetylase inhibitors.
authors.affiliation: Department of Biological Sciences, University of Notre Dame,                     Notre Dame, IN 46556, USA.
authors.forename: Andrew Kekapa'a
authors.initials: AK
authors.lastname: Knutson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Welsh
authors.forename: Travis
authors.initials: T
authors.lastname: Taylor
authors.forename: Somdutta
authors.initials: S
authors.lastname: Roy
authors.forename: Wei-Lin Winnie
authors.initials: WL
authors.lastname: Wang
authors.forename: Martin
authors.initials: M
authors.lastname: Tenniswood
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016158:Genes, p53 / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D000077337:Vorinostat
chemical_list: C531199:7-phenyl-2,4,6-heptatrienoylhydroxamic acid; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat