The Histone Deacetylase SIRT6 Is a Tumor Suppressor that Controls Cancer Metabolism

• Published in: Cell 2012-12, Vol.151 (6), p.1185-1199
• Main Authors: Sebastián, Carlos, Zwaans, Bernadette M.M., Silberman, Dafne M., Gymrek, Melissa, Goren, Alon, Zhong, Lei, Ram, Oren, Truelove, Jessica, Guimaraes, Alexander R., Toiber, Debra, Cosentino, Claudia, Greenson, Joel K., MacDonald, Alasdair I., McGlynn, Liane, Maxwell, Fraser, Edwards, Joanne, Giacosa, Sofia, Guccione, Ernesto, Weissleder, Ralph, Bernstein, Bradley E., Regev, Aviv, Shiels, Paul G., Lombard, David B., Mostoslavsky, Raul
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cell Proliferation; Down-Regulation; Fibroblasts - metabolism; Gene Knockout Techniques; Glycolysis; Histone deacetylase; Humans; Metabolism; Mice; Mice, Nude; Mice, SCID; Molecular modelling; Myc protein; Neoplasm Transplantation; Neoplasms - metabolism; Oncogenes; Prognosis; Proto-Oncogene Proteins c-myc - metabolism; Ribosomes; Sirtuins - genetics; Sirtuins - metabolism; Survival; Transcription; Transcription, Genetic; Transplantation, Heterologous; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumorigenesis
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.10.047

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. [Display omitted] ► SIRT6 is a tumor suppressor that regulates cancer metabolism ► SIRT6 can lead to tumor formation even in the absence of oncogene activation ► SIRT6 levels predict tumor-free survival time in human cancers ► Inhibition of glycolysis in SIRT6-deficient cells abrogates tumor formation The loss of Sirt6 promotes the metabolic reprogramming of cancer cells by increasing aerobic glycolysis and ribosome biosynthesis.