SIRT1-mediated transcriptional regulation of SOX2 is important for self-renewal of liver cancer stem cells
SIRT1-mediated transcriptional regulation of SOX2 is important for self-renewal of liver cancer stem cells
复制标题
SIRT1介导的SOX2转录调控对肝癌干细胞的自我更新具有重要意义
DOI：
10.1002/hep.28690
复制
发表时间：
2016-09-01
期刊：
影响因子：
13.5
通讯作者：
Qian, Cheng
中科院分区：
文献类型：
--
作者：
Liu, Limei;Liu, Chungang;Qian, Cheng
肝细胞癌（HCC）是一种高度侵袭性的肝脏肿瘤，含有癌症干细胞（CSC），参与肿瘤侵袭、治疗耐药性和肿瘤复发，导致预后不良和治疗选择有限。组蛋白去乙酰化酶sirtuin 1（SIRT 1）已被证明在人类癌症中上调;然而，其在肝CSC中的作用尚不清楚。在本研究中，我们探讨了SIRT 1在肝CSCs中的生物学功能。我们的数据表明，SIRT 1在肝CSC中高度表达，并在分化过程中降低。此外，高水平的SIRT 1预测HCC患者的生存概率降低。SIRT 1负责维持肝脏CSCs的自我更新和致瘤性，外源性SIRT 1过表达可恢复非CSCs的自我更新。我们证明了SOX 2是SIRT 1介导的肝CSC自我更新和致瘤潜力的主要下游调节因子。从机制上讲，SIRT 1通过基于染色质的表观遗传变化来调节SOX 2基因的转录，这取决于DNA甲基化。这种作用是通过组蛋白修饰的交替和与DNA甲基转移酶3A的相互作用，导致SOX 2启动子的超甲基化来实现的。此外，我们证明了胰岛素生长因子信号通过增加SIRT 1蛋白稳定性在维持SIRT 1表达中起重要作用。结论：这些发现强调了SIRT 1在肝CSC生物学中的重要性，并表明SIRT 1可能作为HCC治疗的分子靶点。（肝病学2016;64：814-827）
Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs), which participate in tumor invasion, therapeutic resistance, and tumor relapse leading to poor outcome and limited therapeutic options. Histone deacetylatase sirtuin 1 (SIRT1) has been shown to be up-regulated in human cancers; however, its role in liver CSCs is unknown. In this study, we explored the biological functions of SIRT1 in liver CSCs. Our data show that SIRT1 is highly expressed in liver CSCs and decreases during differentiation. In addition, high levels of SIRT1 predict a decreased probability of survival in patients with HCC. SIRT1 is responsible for the maintenance of self-renewal and tumorigenicity of liver CSCs, and overexpression of exogenous SIRT1 can restore self-renewal of non-CSCs. We demonstrated that SOX2 is a main downstream regulator of SIRT1-mediated self-renewal and tumorigenicity potential of liver CSCs. Mechanistically, SIRT1 regulates transcription of the SOX2 gene by way of chromatin-based epigenetic changes, which are dependent on DNA methylation. This effect is achieved by alternation of histone modification and interaction with DNA methyltransferase 3A, resulting in hypermethylation of SOX2 promoter. Furthermore, we demonstrated that insulin growth factor signaling plays an important role in maintaining SIRT1 expression through increased SIRT1 protein stability. Conclusions: These findings highlight the importance of SIRT1 in the biology of liver CSCs and suggest that SIRT1 may serve as a molecular target for HCC therapy. (Hepatology 2016;64:814-827)