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

Yi Hsuan Hsieh, Ih Jen Su, Chia Jui Yen, Ting Fen Tsai, Hung Wen Tsai, Han Ni Tsai, Yu Jun Huang, Yen Yu Chen, Yu Lin Ai, Lin Yuan Kao, Wen Chuan Hsieh, Han Chieh Wu, Wenya Huang

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16 Citations (Scopus)

Abstract

Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S2 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-S2 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 cyclindependent kinase inhibitor p27Kip1, which serves as a marker for pre-S2 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-S2 mutant LHBS-induced degradation of p27Kip1, which, in turn, recovered the normal cell cycle checkpoint. The pre-S2 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-S2 mutant oncoprotein-induced HCC. In conclusion, this study provides the mechanism of histone deacetylase (HDAC) inhibitor in preventing the pre-S2 mutant-induced oncogenic phenotype. The HDAC inhibitor SAHA is therefore a potential chemopreventive agent for high-risk chronic HBV patients who may develop HCC.

Original languageEnglish
Pages (from-to)475-485
Number of pages11
JournalCarcinogenesis
Volume34
Issue number2
DOIs
Publication statusPublished - 2013 Feb

All Science Journal Classification (ASJC) codes

  • Cancer Research

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