Sirtuin1调节β-catenin乙酰化在肝癌干细胞自我更新中的作用及分子机制

It has been proposed that cancer stem cells(CSCs) are responsible for tumor progression, drug resistance, recurrence and metastasis. Our study has shown that histone deacetylase Sirtuin 1 (Sirt1) can be not only as a prognostic indicator in liver cancer but also involved in liver cancer stem cells self-renewal . Further research found that the interference of Sirt1 down-regulated β-catenin and affect it's localization within the nuclear,but the mechanism is not clear. In this study,we will explore the mechanisms of Sirt1 regulates β-catenin acetylation, as well as the role β-catenin acetylation plays in liver cancer stem cell self-renewal. The results of this study will help to clarify a completely new mechanism based on the Wnt signaling pathway to regulates cancer stem cell self-renewal, and develop small molecule compounds or inhibitors of liver cancer stem cells,which will construct a theoretical foundation and experimental support for the development and screening effects.

肿瘤干细胞（cancer stem cells，CSCs）是肿瘤发生、演进、治疗抵抗、复发以及转移的根源。本项目前期研究表明，去乙酰化酶Sirtuin1(Sirt1)不但在肝癌中可作为预后的指标，而且参与肝癌干细胞的自我更新。进一步的研究发现，在肝癌干细胞中干扰Sirt1的表达，导致β-catenin的表达水平降低和改变其在细胞内的核定位。然而，Sirt1调节β-catenin的具体机制尚不清楚。因此，本项目拟在前期研究的工作基础上，着重研究Sirt1调节β-catenin的乙酰化的调控机制，以及β-catenin乙酰化在肝癌干细胞自我更新中的分子作用机制。该研究成果将有助于阐明一项全新的基于Wnt信号通路调节肿瘤干细胞自我更新的机制，而且为开发和筛选作用于肝癌干细胞的小分子化合物或抑制剂奠定理论基础和实验支撑。

本研究课题前期建立的以Nanog为标记的肝癌干细胞模型上，阐明了SIRT1在肝癌干细胞自我更新调控中发挥的重要作用。而Nanog作为β-catenin下游的效应分子，SIRT1通过降低β-catenin蛋白乙酰化修饰状态，促进Nanog的表达，从而维持肝癌干细胞自我更新及肿瘤的形成。进一步研究发现，SIRT1转录调控SOX2的表达，维持肝癌干细胞的自我更新及肿瘤的形成；且IGF维持SIRT1蛋白稳定性，抑制其蛋白泛素化降解。本项目研究成果为肝癌的治疗提供了新的靶点，具有重要意义。