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

Abstract

Abstract. Hepatitis B virus X (HBX) protein has been reported to induce upregulation of β-catenin, a known protooncogene, 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.

Human Viral Oncogenesis: A Cancer Hallmarks Analysis

“…HBx and HCV activate histone deacetylase 1 (HDAC1) and up-regulated metastasis associated protein 1 (MTA-1) (Yoo et al, 2003), both of which contribute to HCC. HCV core promoted steatosis and HBx induced β-catenin, in part, by attenuating expression of SIRT1, an NAD dependent histone deacetylase (Srisuttee et al, 2012). When glucose is plentiful, NAD is converted to NADH, and SIRT1 is inhibited, so these viruses may mimic conditions that promote tumor cell growth via epigenetic modification of host gene expression.…”

Genetic alterations in hepatocellular carcinoma: An update

“…These findings suggest that β -catenin mutations are associated with the etiology of the HCC, which might be explained in part by actions of the HCV core protein synergizing Wnt-induced stabilization and the accumulation of β-catenin, perhaps playing an important role in the pathogenesis of HCV[249]. In HCC occurring in association with HBV, patients display β-catenin activation, which is induced in a mutation-dependent manner by the expression of the HBx protein[250]. Furthermore, one explanation for why β -catenin mutations tend to occur in non-HBV-associated casesis that AXIN mutations (and rarely β -catenin mutations) are mainly found in chromosome-unstable tumors associated with HBV infections, and β -catenin mutations are mainly found in non-HBV, well-differentiated, chromosome-stable tumors[251].…”

Sirtuins: guardians of mammalian healthspan

“…Conversely, evidence primarily from mouse models supports a role for SIRT1 as a tumor suppressor, where SIRT1 promotes the maintenance of genome stability [112], and inhibition of cell growth via survivin (an inhibitor of apoptosis), β-catenin, and other pathways [113, 114]. Consequently, the incidence of spontaneous carcinomas and sarcomas is reduced in Sirt1 transgenic mice [33].…”