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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Blotting, Western
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COP9 Signalosome Complex
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Carcinoma, Hepatocellular / etiology
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / prevention & control*
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Cell Cycle / drug effects
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Proliferation / drug effects*
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Cytoplasm / drug effects
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Cytoplasm / metabolism
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Female
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Fluorescent Antibody Technique
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Hepatitis B Surface Antigens / genetics
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Hepatitis B Surface Antigens / metabolism*
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Hepatitis B virus / drug effects
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Hepatitis B, Chronic / complications
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Hepatitis B, Chronic / prevention & control*
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Hepatitis B, Chronic / virology
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Hydroxamic Acids / pharmacology*
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Immunoenzyme Techniques
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Liver Neoplasms / etiology
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Liver Neoplasms / metabolism
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Liver Neoplasms / prevention & control*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutant Proteins / genetics
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Mutant Proteins / metabolism
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Mutation / genetics*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Peptide Hydrolases / genetics
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Peptide Hydrolases / metabolism
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Protein Precursors / genetics
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Protein Precursors / metabolism*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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TATA Box Binding Protein-Like Proteins / genetics
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TATA Box Binding Protein-Like Proteins / metabolism
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Two-Hybrid System Techniques
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Vorinostat
Substances
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Hepatitis B Surface Antigens
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Intracellular Signaling Peptides and Proteins
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Mutant Proteins
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Nuclear Proteins
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Protein Precursors
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RNA, Messenger
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TATA Box Binding Protein-Like Proteins
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TBPL2 protein, human
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presurface protein 2, hepatitis B surface antigen
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Cyclin-Dependent Kinase Inhibitor p27
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Vorinostat
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Peptide Hydrolases
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COPS5 protein, human
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COP9 Signalosome Complex