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.
Bibliographical noteFunding Information:
This work was supported by NIH awards GM093072-01 and DK088190-01A1 (R.M.) and GM101171 (D.B.L.), the Sidney Kimmel Cancer Research Foundation (R.M.), the Richard D. and Katherine M. O'Connor Research Fund of the University of Michigan Comprehensive Cancer Center (D.B.L.), the Nathan Shock Center (AG013283; D.B.L.), and the Pardee Foundation (D.B.L.). R.M. is a Howard Goodman Scholar and an MGH Research Scholar. D.B.L. is a New Scholar in Aging of the Ellison Medical Foundation. C.S. is the recipient of a Beatriu de Pinos Postdoctoral Fellowship (Generalitat de Catalunya). M.G. is supported by a National Defense Science and Engineering Graduate Fellowship. D.T. is the recipient of the Brain Power for Israel Foundation. C.C. is supported by a Fellowship from the Fondazione Umberto Veronesi. A.R. is supported by a P50HG006193 from the NHGRI Center of Excellence in Genome Science. D.B.L. would like to thank Dr. Chuxia Deng (NIDDK/NIH) for the floxed SIRT6 mouse strain. We thank Nabeel Bardeesy, Eric Fearon, Alexandros Tzatsos, Polina Paskaleva, Kevin Haigis, Agustina D'Urso, Marco Bezzi, and the Mostoslavsky and Lombard labs for technical advice, reagents, and helpful discussions. We thank the ENCODE Chromatin Project at the Broad Institute for data sharing. R.M. is a member of Sirtris scientific advisory board.