WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, Republic of Korea.
Oncol Rep. 2012 Jul;28(1):276-82. doi: 10.3892/or.2012.1798. Epub 2012 May 4.
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.
乙型肝炎病毒 X (HBX) 蛋白已被报道可诱导 p53 基因敲除和 p53 突变的肝细胞系中β-连环蛋白（一种已知的原癌基因）的上调，这是一种 GSK-3β 依赖性的方式，也是通过与腺瘤性结肠息肉病的相互作用，从而防止β-连环蛋白降解。在这项研究中，我们描述了 HBX 介导β-连环蛋白上调的一种新机制。我们观察到 HBX 与 SIRT1 相互作用，SIRT1 是一种 III 类组蛋白去乙酰化酶。此外，HBX 的存在减弱了 SIRT1 与β-连环蛋白之间的相互作用，从而保护β-连环蛋白免受 SIRT1 的抑制作用。用 siRNA 减少 SIRT1 或用烟酰胺抑制 SIRT1 活性可上调β-连环蛋白蛋白水平。相反，用白藜芦醇增强 SIRT1 活性会降低β-连环蛋白蛋白水平。此外，在稳定表达 HBX 的 Hep3B 细胞中，SIRT1 的过表达或用白藜芦醇处理增强了对阿霉素诱导的细胞凋亡的敏感性，表明 SIRT1 的上调可能是治疗乙型肝炎相关肝细胞癌的一种策略。基于这些结果，我们提出 HBX 通过隔离 SIRT1 来上调β-连环蛋白，从而导致抗癌药物治疗耐药。
