SIRT6, a novel direct transcriptional target of FoxO3a, mediates colon cancer therapy
SIRT6, a novel direct transcriptional target of FoxO3a, mediates colon cancer therapy
复制标题
SIRT6 是 FoxO3a 的新型直接转录靶标，介导结肠癌治疗
DOI：
10.7150/thno.29724
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhang, Lingling
中科院分区：
文献类型：
--
作者：
Zhang, Yingjie;Nie, Liming;Zhang, Lingling
SIRT6， NAD+依赖的去乙酰化酶sirtuin 6，最近被证明可以抑制几种类型癌症的肿瘤生长。结肠癌是一种具有高发病率和高死亡率的具有挑战性的癌症。然而，SIRT6是否在结肠肿瘤发生中起直接作用及其潜在机制尚不清楚。方法：为了探讨SIRT6在结肠癌中的作用，我们首先分析了50例结直肠癌（CRC）患者的标本。我们制备了shSIRT6 LoVo细胞和异种移植小鼠，以揭示SIRT6在细胞凋亡和肿瘤生长中的重要作用。为了探索SIRT6调控的潜在机制，我们对活细胞进行了FRET和实时荧光成像、实时PCR、免疫沉淀、免疫组织化学、流式细胞术和荧光素酶报告基因检测。结果：患者标本中SIRT6的表达水平低于正常对照，SIRT6水平较高的患者预后较好。在这里，我们发现转录因子FoxO3a是SIRT6的直接上游，并正向调节SIRT6的表达，进而通过激活Bax和线粒体途径促进细胞凋亡。功能研究表明，Akt失活增加FoxO3a活性，增强其与SIRT6启动子的结合，导致SIRT6表达升高。敲除SIRT6可消除凋亡反应，并赋予对BKM120治疗的抗性。常规药物联合治疗显示出协同的化学增敏作用，在体内和体外都是sirt6依赖性的。结论：研究结果揭示了SIRT6作为一种潜在的结肠癌生物标志物，以及其通过Akt/FoxO3a通路转录和表达的机制。
SIRT6, NAD+-dependent deacetylase sirtuin 6, has recently shown to suppress tumor growth in several types of cancer. Colon cancer is a challenging carcinoma associated with high morbidity and death. However, whether SIRT6 play a direct role in colon tumorigenesis and the underlying mechanism are not understood. Methods: To investigate the role of SIRT6 in colon cancer, we firstly analyzed the specimens from 50 colorectal cancer (CRC) patients. We generated shSIRT6 LoVo cells and xenograft mouse to reveal the essential role of SIRT6 in cell apoptosis and tumor growth. To explore the underlying mechanism of SIRT6 regulation, we performed FRET and real-time fluorescence imaging in living cells, real-time PCR, immunoprecipitaion, immunohistochemistry, flow cytometry and luciferase reporter assay. Results: The expression level of SIRT6 in patients' specimens is lower than that of normal controls, and patients with higher SIRT6 level have a better prognosis. Here, we identified that transcriptional factor FoxO3a is a direct up-stream of SIRT6 and positively regulated SIRT6 expression, which in turn, promotes apoptosis by activating Bax and mitochondrial pathway. Functional studies reveal that Akt inactivation increases FoxO3a activity and augment its binding to SIRT6 promoter, leading to elevated SIRT6 expression. Knocking down SIRT6 abolished apoptotic responses and conferred resistance to the treatment of BKM120. Combinational therapies with conventional drugs showed synergistic chemosensitization, which was SIRT6-dependent both in vitro and in vivo. Conclusion: The results uncover SIRT6 as a new potential biomarker for colon cancer, and its unappreciated mechanism about transcription and expression via Akt/FoxO3a pathway.