title: Histone deacetylase inhibitor suberoylanilide hydroxamic acid suppresses the pro-oncogenic effects induced by hepatitis B virus pre-S2 mutant oncoprotein and represents a potential chemopreventive agent in high-risk chronic HBV patients.
abstract: Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S(2) mutant large HBV surface antigen (LHBS) in type II ground glass hepatocytes (GGHs) has been recognized as an emerging viral oncoprotein; it directly interacts with the c-Jun activation domain-binding protein 1 (JAB1) and subsequently causes hyperphosphorylation of the tumor-suppressor retinoblastoma and, consequently, leads to disturbed cell cycle progression. The interaction of the pre-S(2) mutant LHBS with JAB1 could provide a potential target for chemoprevention. In this study, we found that the preneoplastic type II GGHs showed a significant decrease of the cyclin-dependent kinase inhibitor p27(Kip1), which serves as a marker for pre-S(2) mutant-JAB1 complex formation. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) elevated expression of the tumor-suppressor thioredoxin-binding protein 2 (TBP2), which subsequently enhanced the JAB1-TBP2 interaction and abolished the pre-S(2) mutant LHBS-induced degradation of p27(Kip1), which, in turn, recovered the normal cell cycle checkpoint. The pre-S(2) mutant LHBS-induced pro-oncogenic effects: increased cell proliferation, nuclear/cytoplasmic ratio and proliferating cell nuclear antigen expression, were all greatly ameliorated after SAHA treatments, which suggested SAHA as a promising chemopreventive agent for the pre-S(2) mutant oncoprotein-induced HCC. In conclusion, this study provides the mechanism of histone deacetylase (HDAC) inhibitor in preventing the pre-S(2) mutant-induced oncogenic phenotype. The HDAC inhibitor SAHA is therefore a potential chemopreventive agent for high-risk chronic HBV patients who may develop HCC.
authors.affiliation: The Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University,  Tainan, Taiwan.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Hsieh
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Tsai
authors.forename: Han-Ni
authors.initials: HN
authors.lastname: Tsai
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Huang
authors.forename: Yen-Yu
authors.initials: YY
authors.lastname: Chen
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Ai
authors.forename: Lin-Yuan
authors.initials: LY
authors.lastname: Kao
authors.forename: Wen-Chuan
authors.initials: WC
authors.lastname: Hsieh
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Wu
authors.forename: Wenya
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000075686:COP9 Signalosome Complex; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000187:drug effects; D019694:Hepatitis B, Chronic / Q000150:complications / Q000517:prevention & control* / Q000821:virology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D035182:TATA Box Binding Protein-Like Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D000077337:Vorinostat
chemical_list: D006514:Hepatitis B Surface Antigens; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D035182:TATA Box Binding Protein-Like Proteins; C480637:TBPL2 protein, human; C050807:presurface protein 2, hepatitis B surface antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077337:Vorinostat; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex