Colorectal carcinoma (CRC) is the third leading cause of cancer morbidity and mortality in the United States. Familial Adenomatous Polyposis (FAP) represents one of the most common syndromes associated with high penetrant hereditary CRC. 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. 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., 2006; Zhong et al., 2010). In this proposal, we will study the role of SIRT6 in colorectal cancer cells. We hypothesize that colon cancer cells might selectively down-modulate SIRT6 to aquire a selective advantage in order to grow under conditions of aerobic glycolytic metabolism. Indeed, our preliminary results indicate that loss of SIRT6 provides tumorigenic potential to otherwise normal cells, modulating glycolysis and by- passing classical oncogenic pathways. Furthermore, SIRT6 levels are reduced in human tumors, predominantly in colon cancers. In this proposal, we will determine the precise role for SIRT6 in controlling glucose metabolism and the Warburg effect in the context of APC-dependent colorectal cancers. Specifically, we will 1) Study the role of SIRT6 in controlling the switch to glycolytic metabolism in colorectal cancer cells 2) Evaluate the role of SIRT6 in colon cancer in vivo using a conditional allele of SIRT6 in the context of a murine model of colorectal cancer 3) Determine the role of SIRT6 during the early events of APC-mediated cellular transformation using intestinal organoids derived from human FAP-specific induced-pluripotent stem (iPS) cells. Overall, our results should provide new insights into the molecular mechanisms regulating colon cancer metabolism. In this context, modulation of SIRT6 activity could provide us in the future with a potential therapeutic approach to tackle cancer development.

Public Health Relevance

Colorectal cancer is the third leading cause of cancer morbidity and mortality in the US. One hallmark of cancer cells is their particular metabolism, where sugars are utilized mainly to produce lactate instead of energy through mitochondria (Warburg Effect), with recent studies arguing that such dependency on sugars represents a potential Achilles' heel for tumors. We have found that a protein from the sirtuin deacetylase family, SIRT6, is a critical regulator of energy metabolism, specifically controlling glucose utilization in cells. In this proposal, we will investigate the role of SIRT6 in controlling metaboism in colorectal cancer cells; strikingly, our preliminary results suggest that colon cancer cells rel highly on sugar metabolism, and such a dependency appears to be specifically regulated by SIRT6, providing us in the future with a putative therapeutic approach to tackle metabolism in these oftenly devastating cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA175727-05
Application #
9399630
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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Sociali, Giovanna; Magnone, Mirko; Ravera, Silvia et al. (2017) Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model. FASEB J 31:3138-3149
Choi, Jiho; Clement, Kendell; Huebner, Aaron J et al. (2017) DUSP9 Modulates DNA Hypomethylation in Female Mouse Pluripotent Stem Cells. Cell Stem Cell 20:706-719.e7
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Zhang, Lei; Capilla, Amalia; Song, Weiye et al. (2017) Oblique scanning laser microscopy for simultaneously volumetric structural and molecular imaging using only one raster scan. Sci Rep 7:8591
Sebastián, Carlos; Mostoslavsky, Raul (2017) The Various Metabolic Sources of Histone Acetylation. Trends Endocrinol Metab 28:85-87
Kugel, Sita; Sebastián, Carlos; Fitamant, Julien et al. (2016) SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. Cell 165:1401-1415
Etchegaray, Jean-Pierre; Mostoslavsky, Raul (2016) Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes. Mol Cell 62:695-711
Kugel, Sita; Feldman, Jessica L; Klein, Mark A et al. (2015) Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer. Cell Rep 13:479-488
Sebastián, Carlos; Mostoslavsky, Raul (2015) The role of mammalian sirtuins in cancer metabolism. Semin Cell Dev Biol 43:33-42

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