Abstract SY11-02: The role of the histone deacetylase SIRT6 in glucose homeostasis and cancer

Abstract

Abstract Efficient glucose metabolism is critical for maintaining cellular viability. Under normal nutrient and oxygen conditions, glucose is converted to pyruvate, entering the mitochondria for oxidative phosphorylation and ATP production. Under hypoxia or nutrient stress, metabolism is switched to glycolysis, increasing lactate production and reducing mitochondrial respiration. This switch is critical to maintain cells during periods of starvation or hypoxia; furthermore, recent studies indicate that modulating this switch proved beneficial under chronic glucose imbalance, such as in patients with type II diabetes, and it also plays a critical role in cancer metabolism, as defined by Otto Warburg decades ago. Little is known whether chromatin plays a role in carbohydrate flux. The yeast Sir2 protein is an NAD-dependent histone deacetylase that senses the metabolic status of the cell and functions as a chromatin silencer to promote lifespan and genomic stability. Recently, we discovered that the mammalian SIRT6 is a chromatin factor that influences glucose metabolism and DNA repair. In mice, SIRT6-deficiency provokes a profound and lethal hypoglycemia which culminates in accelerated death. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production and decreased mitochondrial activity. Our results indicate that SIRT6 directly regulates expression of several key glycolytic genes. In this context, SIRT6 functions at chromatin to attenuate a Hif1α transcriptional nutrient response. SIRT6 co-represses Hif1α, acting as a histone H3 lysine9 (H3K9) deacetylase to inhibit expression of Hif1α-target gene promoters (Zhong et al, 2010). In the absence of SIRT6, H3K9 acetylation is enhanced in these promoters, triggering a Hif1α-dependent glycolytic switch, a response that appears critical in order to maintain cells under conditions of nutrient stress. In this context, our new studies indicate that this “glycolytic switch” observed in the absence of SIRT6 provides a growth advantage in the context of tumorigenesis. Potential mechanistic implications will be further discussed. Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R.E., Vadysirisack, D.D., Guimaraes, A., Marinelli, B., Wikstrom, J.D., Nir, T., Clish, C.B., Vaitheesvaran, Iliopoulos, O., B., Kurland, I., Dor, Y., Weissleder, R., Shirihai, O.S., Ellisen, L., Espinosa, J.M., and Mostoslavsky, R. (2010). The histone deacetylase SIRT6 regulates glucose homeostasis via Hif1a. Cell, 140, 280-293. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY11-02. doi:10.1158/1538-7445.AM2011-SY11-02