title: Loss of RUNX3 expression by histone deacetylation is associated with biliary tract carcinogenesis.
abstract: RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region frequently inactivated through hypermethylation, histone modulation, and other processes in various human tumors. In this study, to elucidate a causal link between RUNX3 expression and biliary tract cancer, we investigated 17 human biliary cancer specimens. In addition, to examine roles of RUNX3 in biliary tract cancer, we restored silenced RUNX3 in the human biliary cancer cell line Mz-ChA-2 using a histone deacetylase inhibitor. Thirteen of 17 human cancer specimens exhibited suppressed RUNX3 expression compared with normal biliary ducts. Moreover, the decreased RUNX3 expression was related to a lower accumulation of acetylated histone H3 associated with RUNX3. In in vitro experiments, vorinostat, a member of a new class of highly potent histone deacetylase inhibitors, restored RUNX3 expression in Mz-ChA-2 cells. Furthermore, vorinostat-induced RUNX3 significantly enhanced p21 expression and growth inhibition of Mz-ChA-2 cells through restoration of TGF-β signaling. These data suggest the significance of histone deacetylation-associated suppression of RUNX3 expression in biliary tract carcinogenesis. Furthermore, vorinostat might hold promise for treating biliary tract cancer through enhancement of TGF-β signaling by restoration of RUNX3.
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Shio
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shiokawa
authors.forename: Koji
authors.initials: K
authors.lastname: Kitamura
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000107:Acetylation; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D050677:Core Binding Factor Alpha 3 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C493729:Runx3 protein, human; D000077337:Vorinostat; D008156:Luciferases