Abstract SY20-01: Linking epigenetics, metabolism, and cancer: Lessons from SIRT6

Abstract In recent years, chromatin regulators have emerged as key modulators in cancer. These factors could work as both tumor suppressors and oncogenes, providing plasticity to cancer cells as they adapt to overcome the host responses. In recent years, we discovered that the mammalian histone deacetylase SIRT6 is a key chromatin factor, modulating expression of metabolic, developmental, and ribosomal protein genes. In recent studies, we identified a loss of function mutation in SIRT6 behind a human syndrome of perinatal lethality. In the context of cancer, we found SIRT6 to act as a robust tumor suppressor, by modulating glucose metabolism. As Otto Warburg described decades ago, cancer cells exhibit glycolytic metabolism, where pyruvate, instead of contributing to ATP production in the mitochondria, is converted to lactate even under normoxia conditions. We found SIRT6 as the first chromatin factor in charge of suppressing the Warburg effect in colon cancer. 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, co-repressing Hif1a and Myc, respectively, and acting as a histone H3 lysine9 (H3K9) and lysine 56 (H3K56) deacetylase to specifically inhibit transcriptional elongation in these genes. Strikingly, we determined in new studies that such glycolytic switch provides an advantage even at the early initiating cancer stem cells stage, in what we identified as the cell-of-origin for the Warburg effect. In addition, we found SIRT6 to act as a robust tumor suppressor in the context of pancreatic cancer. However, in this case, SIRT6 did not influence metabolism, but rather silenced expression of the developmental gene Lin28b, in this way protecting against aggressive undifferentiated pancreatic adenocarcinoma. Our studies highlight the important role epigenetic factors, such as SIRT6, play in protecting against tumor progression by providing “epigenetic plasticity”, inhibiting adaptive responses in transformed cells. References 1. Zhong, L., et al., and Mostoslavsky, R. (2010). The histone deacetylase SIRT6 regulates glucose homeostasis via Hif1a. Cell, 140, 280-293. 2. Sebastian, C., et al. and Mostoslavsky, R. (2012). The Histone Deacetylase SIRT6 is a novel tumor suppressor that controls cancer metabolism. Cell 151, 1185-1199. 3. Kugel., et al. and Mostoslavsky, R. (2016). SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell, 165, 1401-1415. Ferrer et al. 4. Mostoslavsky, R. (2018). An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes & Dev. 32, 373-388 Citation Format: Raul Mostoslavsky. Linking epigenetics, metabolism, and cancer: Lessons from SIRT6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY20-01.