(PQB4)SIRT6 Modulates Cancer Metabolism During Aging

描述(申请人提供)：衰老与生理功能下降和几种疾病的主要发病率有关。其中，罹患癌症的风险随着年龄的增长而急剧增加。事实上，它和心脏病一样，是老年人的第一大死因。除了突变随着年龄的增长而逐渐积累外，人们对衰老过程中癌症发病率增加的分子机制知之甚少。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。有趣的是，在衰老过程中，在几个组织中观察到了这种能量代谢的变化。然而，将癌症、衰老和代谢重编程联系在一起的分子通路仍然缺乏特征性。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，Cell 2006；钟等人，Cell 2010)。最近，我们发现SIRT6是一种有效的肿瘤抑制因子，可以抑制癌症代谢(Sebastian等人，Cell 2012)。SIRT6在细胞中的失活会导致它们的转化，而不会激活主要的致癌途径，在结直肠癌的小鼠模型中，缺乏SIRT6会增加肿瘤的数量、大小和侵袭性。重要的是，所有这些表型都被遗传或化学抑制糖酵解逆转，突出了糖代谢重新编程在肿瘤发生中的驱动作用。在这种情况下，在小鼠中过表达SIRT6可以延长寿命，这一表型可能是由于其肿瘤抑制活性所致。基于这些发现，我们假设在衰老过程中SIRT6的表达减少可以改变组织中的葡萄糖代谢，有利于糖酵解依赖的肿瘤发生和肿瘤生长。在这项资助中，我们将具体：1-研究SIRT6在衰老过程中代谢重新编程中的作用。2-通过调节葡萄糖代谢，确定SIRT6作为肿瘤抑制因子在衰老相关癌症中的作用。SIRT6活性的调节可能为我们未来提供一种潜在的治疗方法，以减少老年人群中的癌症发病率。

DESCRIPTION (provided by applicant): Aging is associated with a decline in physiological functions and a major incidence of several diseases. Among them, the risk of suffering from cancer dramatically increases with age. In fact, together with heart diseases, it represents the first cause of death in elder people. Besides the gradual accumulation of mutations with age, very little is known about the molecular mechanisms involved in the increased cancer incidence during aging. 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. Interestingly, such change in energy metabolism has been observed in several tissues during aging. However, the molecular pathways linking cancer, aging and metabolic reprogramming remain poorly characterized. 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., Cell 2006; Zhong et al., Cell 2010). More recently, we have found that SIRT6 is a potent tumor suppressor that inhibits cancer metabolism (Sebastian et al, Cell 2012). Inactivation of SIRT6 in cells leads to their transformation without the activation of a major oncogenic pathway and, in a mouse model of colorectal cancer, lack of SIRT6 increases the number, size and aggressiveness of tumors. Importantly, all these phenotypes are reversed by genetically or chemically inhibiting glycolysis, highlighting the driving role of glucose metabolism reprogramming in tumorigenesis. In this context, overexpression of SIRT6 in mice extends lifespan, a phenotype that is likely due to its tumor suppressor activity. Based on these findings, we hypothesize that decreased expression of SIRT6 during aging could switch glucose metabolism in tissues, favoring glycolytic-dependent tumorigenesis and tumor growth. In this grant, we will specifically: 1- Study the role of SIRT6 in metabolic reprogramming during aging. 2- Determine the role of SIRT6 as a tumor suppressor in aging-associated cancers by regulating glucose metabolism. Modulation of SIRT6 activity could provide us in the future with a potential therapeutic approach to reduce cancer incidence in the age population.