title: Hepatitis C virus core protein enhances hepatocellular carcinoma cells to be susceptible to oncolytic vesicular stomatitis virus through down-regulation of HDAC4.
abstract: Since hepatitis C virus (HCV) core protein is known to possess potential oncogenic activity, we explored whether oncolytic vesicular stomatitis virus (VSV) could efficiently induce cytolysis in hepatocellular carcinoma cells stably expressing HCV core protein (Hep3B-Core). We found that Hep3B-Core cells were more susceptible to VSV as compared to control (Hep3B-Vec) cells owing to core-mediated inactivation of STAT1 and STAT2 proteins. Core expression induced lower phosphorylation levels of type I IFN signaling proteins such as Tyk2 and Jak1, and a reduced response to exogenous IFN-α, which resulted in susceptibility to VSV. Furthermore, as STAT1 acetylation by switching phosphorylation regulated its activity, the role of STAT1 acetylation in susceptibility of Hep3B-Core cells to VSV was investigated. Treatment with trichostatin A, an inhibitor of histone deacetylase (HDAC), increased STAT1 acetylation but blocked IFN-α-induced phosphorylation of STAT1, leading to increase of susceptibility to VSV. Interestingly, the core protein decreased HDCA4 transcript levels, leading to down-regulation of HDAC4 protein. However, ectopic expression of HDAC4 conversely enforced phosphorylation of STAT1 and hindered VSV replication, indicating that core-mediated reduction of HDAC4 provides a suitable intracellular circumstance for VSV replication. Collectively, we suggest that VSV treatment will be a useful therapeutic strategy for HCV-infected hepatocellular carcinoma cells because HCV core protein suppresses the anti-viral threshold by down-regulation of the STAT1-HDAC4 signaling axis.
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Republic of Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Moon
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Republic of Korea.
authors.forename: Sirichat
authors.initials: S
authors.lastname: Kaowinn
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Republic of Korea.
authors.forename: Il-Rae
authors.initials: IR
authors.lastname: Cho
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Do Sik
authors.initials: DS
authors.lastname: Min
authors.affiliation: Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yong-In, 449-791, Republic of Korea.
authors.forename: Heejoon
authors.initials: H
authors.lastname: Myung
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul, 136-702, Republic of Korea.
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Biology, Faculty of Science, Thakshin University, Phatthalung, 93210, Thailand.
authors.forename: Chutima
authors.initials: C
authors.lastname: Kaewpiboon
authors.affiliation: Center for Molecular Biomedicine, Department of Biochemistry, University of Jena, Jena, 07745, Germany.
authors.forename: Olive H
authors.initials: OH
authors.lastname: Kraemer
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Republic of Korea. Electronic address: younghc@pusan.ac.kr.
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006526:Hepatitis C / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D016896:Treatment Outcome; D054243:Vesicular Stomatitis / Q000821:virology; D018116:Vesiculovirus / Q000502:physiology*; D014758:Viral Core Proteins / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; D014758:Viral Core Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: Acetylation; HDAC4; Phosphorylation; STAT1; VSV; Virotherapy