Hepatitis B virus X (HBX) protein upregulates β-catenin in a human hepatic cell line by sequestering SIRT1 deacetylase

• Published in: Oncology reports Vol. 28; no. 1; pp. 276 - 282
• Main Authors: SRISUTTEE, Ratakorn, SEOK KOH, Sang, OH, Sangtaek, CHUNG, Young-Hwa, SU JIN KIM, MALILAS, Waraporn, BOONYING, Wassamon, CHO, Il-Rae, BYUNG HAK JHUN, ITO, Masafumi, HORIO, Yoshiyuki, SETO, Edward
• Format: Journal Article
• Language: English
• Published: Athens Spandidos 01-07-2012
• Subjects: Antibiotics, Antineoplastic - pharmacology; Apoptosis - drug effects; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Carcinoma, Hepatocellular; Cell Line, Tumor; Doxorubicin - pharmacology; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Liver Neoplasms; Medical sciences; Protein Binding; Sirtuin 1 - metabolism; Trans-Activators - metabolism; Trans-Activators - physiology; Tumors; Up-Regulation; Wnt Signaling Pathway; Antineoplastic agent; Liver; Orthohepadnavirus; Doxorubicin; β-catenin; Isomerases; Cancerology; Hepadnaviridae; Established cell line; Hepatitis B virus; Human; DNA topoisomerase (ATP-hydrolysing); Digestive system; Enzyme; Enzyme inhibitor; Topoisomerase II inhibitor; Protein A; hepatitis B virus X; SIRT1; Virus; Cell death; β Catenin; Anthracyclins; Apoptosis; NAD-dependent deacetylase sirtuin-1
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2012.1798

Hepatitis B virus X (HBX) protein has been reported to induce upregulation of β-catenin, a known proto-oncogene, in p53-knockout and p53-mutant hepatic cell lines both in a GSK-3β-dependent manner and via interaction with adenomatous polyposis coli, which results in protection from β-catenin degradation. In this study, we describe a novel mechanism for HBX-mediated upregulation of β-catenin. We observed that HBX interacts with SIRT1, a class III histone deacetylase. Furthermore, the presence of HBX attenuated the interaction between SIRT1 and β-catenin, leading to protection of β-catenin from the inhibitory action of SIRT1. Reduction of SIRT1 with siRNA or suppression of SIRT1 activity with nicotinamide upregulated β-catenin protein levels. In contrast, enhancement of SIRT1 activity with resveratrol reduced β-catenin protein levels. Furthermore, in Hep3B cells stably expressing HBX, overexpression of SIRT1 or treatment with resveratrol enhanced sensitivity to doxorubicin-induced apoptosis, indicating that upregulation of SIRT1 could be a therapeutic strategy for HBV-related hepatocellular carcinoma. Based on these results, we propose that HBX upregulates β-catenin by sequestering SIRT1, which leads to anticancer drug treatment resistance.