The Role of SIRT6 and Metabolism in APC Mediated Tumorigenesis

描述（由申请人提供）：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）是与高渗透遗传性结直肠癌相关的最常见综合征之一。癌细胞的一个显著特征是它们增加的葡萄糖摄取和依赖有氧糖酵解代谢，这是Otto Warburg几十年前描述的一种现象。虽然它是一种潜在的靶向肿瘤的候选药物，但人们对其控制机制知之甚少。值得注意的是，我们最近发现SIRT6组蛋白去乙酰化酶是糖酵解代谢的中枢调节因子：缺乏SIRT6的细胞会经历剧烈的代谢开关，增加乳酸生成，同时减少线粒体呼吸（Mostoslavsky等人，2006；Zhong等人，2010）。在本课题中，我们将研究SIRT6在结直肠癌细胞中的作用。我们假设结肠癌细胞可能选择性下调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，调节糖酵解并通过经典的致癌途径。此外，SIRT6水平在人类肿瘤中降低，主要是在结肠癌中。在本提案中，我们将确定SIRT6在apc依赖性结直肠癌中控制葡萄糖代谢和Warburg效应中的确切作用。具体而言，我们将1)研究SIRT6在控制结直肠癌细胞糖酵解代谢转换中的作用2)在小鼠结直肠癌模型中使用SIRT6的条件等位基因评估SIRT6在体内结肠癌中的作用3)确定SIRT6在apc介导的细胞转化早期事件中的作用，这些细胞转化来自人类fap特异性诱导多能干细胞（iPS）的肠道类器官。总的来说，我们的研究结果应该为结肠癌代谢调节的分子机制提供新的见解。在这种情况下，SIRT6活性的调节可以在未来为我们提供一种潜在的治疗癌症发展的方法。

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.