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

  • Cell. 2012 Dec 7;151(6):1185-99. doi: 10.1016/j.cell.2012.10.047.
Carlos Sebastián  1 ,  Bernadette M M Zwaans ,  Dafne M Silberman ,  Melissa Gymrek ,  Alon Goren ,  Lei Zhong ,  Oren Ram ,  Jessica Truelove ,  Alexander R Guimaraes ,  Debra Toiber ,  Claudia Cosentino ,  Joel K Greenson ,  Alasdair I MacDonald ,  Liane McGlynn ,  Fraser Maxwell ,  Joanne Edwards ,  Sofia Giacosa ,  Ernesto Guccione ,  Ralph Weissleder ,  Bradley E Bernstein ,  Aviv Regev ,  Paul G Shiels ,  David B Lombard ,  Raul Mostoslavsky
Affiliations
  • 1. The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
PMID: 23217706 DOI: 10.1016/j.cell.2012.10.047
Abstract

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.