Chicago - 10:00 AM - 11:00 AM
The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents:
Raul Mostoslavsky, MD, PhD
Associate Professor, Medicine
Harvard Medical School
The Massachusetts General Hospital
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. 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. Little is known whether chromatin plays a role in carbohydrate flux. Recently, we discovered that the mammalian histone deacetylase SIRT6 is a key chromatin factor modulating glucose metabolism. 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 Hif1 and Myc, and acting as a histone H3 lysine9 (H3K9) and lysine 56 (H3K56) deacetylase to inhibit expression of these genes. In this context, SIRT6 functions as a robust tumor suppressor in colon cancer by inhibiting the Warburg effect (Zhong et al, 2010; Sebastian et al., 2012). Strikingly, we determined in new studies that such glycolytic switch provides an advantage even at the early initiating cancer stem cells stage. 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 inhibiting adaptive responses in transformed cells.