The Role of SIRT6 and Metabolism in APC Mediated Tumorigenesis

描述(申请人提供)：结直肠癌(CRC)是美国癌症发病率和死亡率的第三大原因。家族性腺瘤性息肉病(FAP)是高穿透性遗传性结直肠癌最常见的综合征之一。癌细胞的一个显著特征是它们对葡萄糖的摄取增加，并依赖有氧糖酵解代谢，这是奥托·沃伯格几十年前描述的现象。尽管它是一个潜在的靶向肿瘤的候选者，但人们对它的控制机制知之甚少。值得注意的是，我们最近发现SIRT6组蛋白脱乙酰酶是糖酵解代谢的中央调节因子：缺乏SIRT6的细胞经历了戏剧性的代谢转换，增加了乳酸的产生，同时减少了线粒体的呼吸(Mostola vsky等人，2006；钟等人，2010)。在这项研究中，我们将研究SIRT6在结直肠癌细胞中的作用。我们推测，结肠癌细胞可能选择性地下调SIRT6以获得选择性优势，以便在有氧糖酵解代谢条件下生长。事实上，我们的初步结果表明，SIRT6的缺失为正常细胞提供了致瘤潜力，调节了糖酵解并绕过了经典的致癌途径。此外，人类肿瘤中的SIRT6水平降低，主要是在结肠癌中。在这项提案中，我们将确定SIRT6在控制糖代谢中的确切作用以及APC依赖型结直肠癌中的Warburg效应。具体地说，我们将1)研究SIRT6在控制结直肠癌细胞向糖酵解代谢转换中的作用；2)在小鼠结直肠癌模型的背景下，使用SIRT6的条件等位基因在体内评估SIRT6在结肠癌中的作用；3)确定SIRT6在使用来自人FAP特异性诱导多能干细胞(IPS)的肠道器官介导的APC细胞转化早期事件中的作用。总体而言，我们的结果应该为调节结肠癌新陈代谢的分子机制提供新的见解。在这种背景下，SIRT6活性的调节可能为我们未来提供一种潜在的治疗方法来应对癌症的发展。

DESCRIPTION (provided by applicant): Colorectal carcinoma (CRC) is the third leading cause of cancer morbidity and mortality in the United States. Familial Adenomatous Polyposis (FAP) represents one of the most common syndromes associated with high penetrant hereditary CRC. A prominent feature of cancer cells is their increased glucose uptake and reliance on aerobic glycolytic metabolism, a phenomenon described by Otto Warburg decades ago. Though it is a potential candidate for targeting against tumors, little is known about the mechanisms controlling it. Remarkably, we have recently identified the SIRT6 histone deacetylase as a central regulator of glycolytic metabolism: cells lacking SIRT6 undergo a dramatic metabolic switch, increasing lactate production while reducing mitochondrial respiration (Mostoslavsky et al., 2006; Zhong et al., 2010). In this proposal, we will study the role of SIRT6 in colorectal cancer cells. We hypothesize that colon cancer cells might selectively down-modulate SIRT6 to aquire a selective advantage in order to grow under conditions of aerobic glycolytic metabolism. Indeed, our preliminary results indicate that loss of SIRT6 provides tumorigenic potential to otherwise normal cells, modulating glycolysis and by- passing classical oncogenic pathways. Furthermore, SIRT6 levels are reduced in human tumors, predominantly in colon cancers. In this proposal, we will determine the precise role for SIRT6 in controlling glucose metabolism and the Warburg effect in the context of APC-dependent colorectal cancers. Specifically, we will 1) Study the role of SIRT6 in controlling the switch to glycolytic metabolism in colorectal cancer cells 2) Evaluate the role of SIRT6 in colon cancer in vivo using a conditional allele of SIRT6 in the context of a murine model of colorectal cancer 3) Determine the role of SIRT6 during the early events of APC-mediated cellular transformation using intestinal organoids derived from human FAP-specific induced-pluripotent stem (iPS) cells. Overall, our results should provide new insights into the molecular mechanisms regulating colon cancer metabolism. In this context, modulation of SIRT6 activity could provide us in the future with a potential therapeutic approach to tackle cancer development.