title: Suppressive effect of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) on hepatitis C virus replication.
abstract: The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has a clinical promise for treatment of cancer including hepatocellular carcinoma (HCC). To investigate effect of SAHA on hepatitis C virus (HCV) replication, we treated the HCV replicon cell OR6 with SAHA. HCV replication was significantly inhibited by SAHA at concentrations below 1 μM with no cellular toxicity. Another HDAC inhibitor, tricostatin A, also showed reduction of HCV replication. The microarray analysis and quantitative RT-PCR demonstrated up-regulation of osteopontin (OPN) and down-regulation of apolipoprotein-A1 (Apo-A1) after SAHA treatment. Direct gene induction of OPN and knockdown of Apo-A1 also showed reduction of HCV replication. The liver specific microRNA-122, which is involved in HCV replication, was not affected by SAHA treatment. These results suggest that SAHA has suppressive effect on HCV replication through alterations of gene expression such as OPN and Apo-A1 in host cells. Epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for diseases associated with HCV infection such as chronic hepatitis, liver cirrhosis, and HCC.
authors.affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Tokyo, 1058512, Japan.
authors.forename: Ayami
authors.initials: A
authors.lastname: Sato
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Saito
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakasegawa
authors.forename: Toshihide
authors.initials: T
authors.lastname: Muramatsu
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukuda
authors.forename: Mikiko
authors.initials: M
authors.lastname: Yoneya
authors.forename: Masaki
authors.initials: M
authors.lastname: Kimura
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ebinuma
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Saito
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053495:Osteopontin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053495:Osteopontin; C012589:trichostatin A; D000077337:Vorinostat
keywords: APOLIPOPROTEIN-A1; HEPATITIS C VIRUS; MIR-122; OR6; OSTEOPONTIN; SUBEROYLANILIDE HYDROXAMIC ACID