The Role of SIRT6 and Metabolism in APC Mediated Tumorigenesis

SIRT6 和代谢在 APC 介导的肿瘤发生中的作用

• 批准号: 9208290
• 负责人: Gustavo Mostoslavsky
• 金额: $ 5.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208290
• 关键词: Accounting; Adenomatous Polyposis Coli; Aerobic; Aging; Alleles; Anterior; Automobile Driving; Binding; Biochemical Pathway; Biological Assay; Cancer Etiology; Cancer cell line; Cell Line; Cells; Cellular Metabolic Process; Clinical; Colon; Colon Carcinoma; Colorectal Cancer; Deacetylase; Deacetylation; Dependency; Development; Disease; Energy Metabolism; Enzymes; Event; Exhibits; Family; Future; Gene Expression Profiling; Genes; Genetically Engineered Mouse; Genomics; Glucose; Glutamine; Glycolysis; Health; Histone Deacetylase; Histones; Human; Human Cell Line; In Vitro; Inherited; Intestinal Cancer; Intestinal Neoplasms; Intestines; Large Intestine; Large Intestine Carcinoma; Malignant Epithelial Cell; Malignant Neoplasms; Measurement; Mediating; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Normal Cell; Oncogenes; Oncogenic; Organoids; Pathway interactions; Patients; Phenotype; Physiological; Play; Process; Production; Proteins; Rectum; Regulation; Respiration; Role; Sampling; Site; Small Intestines; Specimen; Stable Isotope Labeling; Syndrome; Technology; Testing; Therapeutic; To specify; Treatment outcome; Tumor Suppressor Genes; United States; Warburg Effect; aerobic glycolysis; base; blood glucose regulation; cancer cell; cell growth; cohort; glucose metabolism; glucose uptake; in vivo; induced pluripotent stem cell; insight; intestinal epithelium; member; metabolomics; metaplastic cell transformation; mortality; mouse model; mutant; novel; promoter; regenerative; response; sugar; targeted treatment; tumor; tumor growth; tumor initiation; tumor metabolism; tumor progression; tumorigenesis; tumorigenic; uptake

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.

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CRC相关的最常见综合征之一。癌细胞的一个突出特征是它们增加的葡萄糖摄取和对有氧糖酵解代谢的依赖，这是奥托瓦尔堡几十年前描述的现象。值得注意的是，我们最近鉴定了SIRT 6组蛋白脱乙酰酶作为糖酵解代谢的中心调节剂：缺乏SIRT 6的细胞经历了戏剧性的代谢转换，增加乳酸盐的产生，同时减少线粒体呼吸（Mostoslavsky et al.，2006; Zhong等人，2010年）。在本提案中，我们将研究SIRT 6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SIRT 6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，SIRT 6的缺失为其他正常细胞提供了致瘤潜力，调节糖酵解并绕过经典的致癌途径。此外，SIRT 6水平在人类肿瘤中降低，主要是在结肠癌中。在这个提议中，我们将确定SIRT 6在APC依赖性结直肠癌中控制葡萄糖代谢和瓦尔堡效应的确切作用。具体地说，我们将1）研究SIRT 6在控制结肠直肠癌细胞中糖酵解代谢转换中的作用2）在结肠直肠癌的鼠模型的背景下使用SIRT 6的条件等位基因评估SIRT 6在体内结肠癌中的作用3）使用来源于人FAP的肠类器官确定SIRT 6在APC介导的细胞转化的早期事件期间的作用。特异性诱导多能干细胞（iPS）。总的来说，我们的研究结果应该为调节结肠癌代谢的分子机制提供新的见解。在这种情况下，SIRT 6活性的调节可以在未来为我们提供一种潜在的治疗方法来解决癌症的发展。