Abstract CN11-01: The histone deacetylase SIRT6 is a key modulator of cancer metabolism

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, a switch known to play an important role in cancer cells, as defined by Otto Warburg decades ago. Little is known whether chromatin plays a role in carbohydrate flux. Recently, we discovered that the mammalian histone deacetylase SIRT6 is a chromatin factor that influences glucose metabolism and DNA repair. 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 and ribosomal genes. SIRT6 co-represses Hif1α, acting as a histone H3 lysine9 (H3K9) and lysine 56 (H3K56) deacetylase to inhibit expression of their target genes, and functioning as a tumor suppressor to inhibit the Warburg effect (Zhong et al, 2010; Sebastian et al., 2012). Further, in recent studies we identified SIRT6 as a key protector against genomic instability, anchoring the chromatin remodeler SNF2H to sites of DNA breaks (Toiber et al., 2013). Our work identified SIRT6 as a critical chromatin deacetylase, sitting on a nodal point between epigenetics, DNA repair and metabolism, in turn functioning as an important tumor suppressor. Zhong, L., D9Urso, 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 Hif1α;. Cell, 140, 280-293. Sebastian, C., Zwaans, B.M., Silberman, D.M., Gymrek, M.A., Goren, A., Zhong, L., Ran, O., Truelove, J., Guimaraes, A.R., Toiber, D., Cosentino, C., Greenson, J.K., MacDonald, A.I., McGlynn, L., Maxwell, F., Edwards, J., Giacosa, S., Guccione, E., Weisledder, R., Bernstein, B.E., Regev, A., Shiels, P.G., Lombard, D.B. and Mostoslavsky, R. (2012). The Histone Deacetylase SIRT6 is a novel tumor suppressor that controls cancer metabolism. Cell 151, 1185-1199. Toiber, D., Erdel, F., Bouazoune, K., Silberman, D.M., Zhong, L., Mulligan, P., Sebastian, C., Cosentino, C., Martinez-Pastor, B., Giacosa, S., D9Urso, A., Naar, A.M., Kingston, R., Rippe, K., and Mostoslavsky, R. (2013). SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Molecular Cell 51, 454-468. Citation Format: Raul Mostoslavky. The histone deacetylase SIRT6 is a key modulator of cancer metabolism. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN11-01.