SIRT6调控Bax凋亡信号通路促进肝癌形成的作用机制研究

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. In China, HCC is the second most common cause of cancer mortality. Despite its high prevalence and inferior prognosis in general, our understanding of the pathogenesis of this cancer is very limited. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and that current systemic chemotherapeutics are mostly inefficacious. A better understanding on the molecular basis of HCC is therefore urgently required to facilitate development of new therapeutic strategies. Sirtuin 6(SIRT6) is a class III histone deacetylase implicated in the development of various cancer,yet its role in carcinogenesis of HCC remains uncertain. We showed that SIRT6 expression is upregulated in the majority of human HCC cell lines and tumor tissues. Functional studies revealed that gene silencing of SIRT6 significantly suppressed proliferation of HCC cells that was associated with a remarkable upregulation of Bax expression. Our preliminary data therefore revealed a novel role of SIRT6 in the regulation of Bax-mediated apoptosis,which plays a major role in HCC proliferation. The central theme of this proposal is thus to elucidate the molecular basis of SIRT6 in regulating the Bax-mediated pathway. We will also use animal model to evaluate if suppression of SIRT6 will mitigate HCC growth. Our proposed studies therefore hold value in providing a better understanding on the role of SIRT6 in HCC tumorigenesis, and will impact on the future development of SIRT6 inhibitors as HCC therapeutics.

沉默信息调节因子6( SIRT6)是烟碱胺腺嘌呤二核苷酸(NAD + )依赖的组蛋白去乙酰化酶,在多种肿瘤的发生发展中发挥着重要的作用，但其在肝癌中的报道非常少。我们的前期研究发现SIRT6在肝癌细胞系和人类肝细胞癌组织中表达明显增高，并且SIRT6沉默能抑制肝癌细胞生长并显著诱导细胞凋亡。我们进一步发现SIRT6能够调控Bax及其下游多个信号分子的表达。因此我们推测SIRT6在肝癌细胞中异常高表达与肝癌细胞恶性增殖能力密切相关，SIRT6基因沉默通过影响Bax的表达或细胞定位，从而激活下游凋亡信号分子，最终诱导肝癌细胞的凋亡。因此本项目进一步研究SIRT6对Bax表达水平，细胞定位，寡聚化及下游信号分子等的影响及相关的分子机制，并在荷瘤小鼠模型上验证SIRT6沉默的抗肿瘤效力。

沉默信息调节因子6( SIRT6)是烟碱胺腺嘌呤二核苷酸(NAD + )依赖的组蛋白去乙酰化酶,在多种肿瘤的发生发展中发挥着重要的作用，但其在肝癌中的报道非常少。本项目研究发现SIRT6在人类肝细胞癌组织中表达明显增高，SIRT6高表达与肿瘤的分期，大小和血管侵袭密切相关；SIRT6高表达的病人生存率显著降低。细胞模型研究发现SIRT6沉默能抑制肝癌细胞生长并显著诱导细胞凋亡。我们进一步发现在肝癌细胞中SIRT6高表达能够抑制促凋亡蛋白Bax依赖的凋亡信号通路的激活。机制解析发现SIRT6能够结合至Bax基因启动子区域，去乙酰化H3K9,抑制转录因子E2F2和p53与Bax启动子区域的结合，最终抑制Bax的表达；另外，在胞质中SIRT6可以结合并降低Ku70的乙酰化修饰水平，增强Ku70与Bax的结合，阻止Bax往线粒体的转位。最后，在裸鼠异位移植瘤模型，SIRT6基因沉默具有显著抑制肿瘤生长的作用。本课题阐明促癌基因SIRT6 对肝癌细胞恶性增殖表型的影响，部分阐明肝癌的发生机制。研究成果将有助于发现新的肝癌诊断、治疗及预后相关因子，从而为开发SIRT6 抑制剂作为潜在的肝癌治疗手段提供有力证据。