The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism

Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism.Fil: Sebastián, Carlos. Harvard Medical School; Estados UnidosFil: Zwaans, Bernardette M. M.. University of Michigan; Estados UnidosFil: Silberman, Dafne Magali. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Gymrek, Melissa. Massachusetts Institute of Technology; Estados UnidosFil: Goren, Alon. Harvard Medical School; Estados Unidos. Massachusetts Institute of Technology; Estados UnidosFil: Zhong, Lei. Harvard Medical School; Estados UnidosFil: Ram, Oren. Harvard Medical School; Estados Unidos. Massachusetts Institute of Technology; Estados UnidosFil: Truelove, Jessica. The Massachusetts General Hospital; Estados UnidosFil: Guimaraes, Alexander R.. The Massachusetts General Hospital; Estados UnidosFil: Toiber, Debra. Harvard Medical School; Estados UnidosFil: Cosentino, Claudia. Harvard Medical School; Estados UnidosFil: Greenson, Joel K.. University of Michigan; Estados UnidosFil: MacDonald, Alasdair I.. University of Glasgow; Reino UnidoFil: McGlynn, Liane. University of Glasgow; Reino UnidoFil: Maxwell, Fraser. University of Glasgow; Reino UnidoFil: Edwards, Joanne. University of Glasgow; Reino UnidoFil: Giacosa, Sofía. Harvard Medical School; Estados UnidosFil: Guccione, Ernesto. Institute of Molecular and Cell Biology; SingapurFil: Weissleder, Ralph. The Massachusetts General Hospital; Estados UnidosFil: Bernstein, Bradley E.. Harvard Medical School; Estados UnidosFil: Regev, Aviv. Harvard Medical School; Estados UnidosFil: Shiels, Paul G.. University of Glasgow; Reino UnidoFil: Lombard, David B.. University of Michigan; Estados UnidosFil: Mostoslavsky, Raul. Harvard Medical School; Estados Unido