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

Carlos Sebastián, Bernadette M M Zwaans, Dafne M. Silberman, Melissa Gymrek, Alon Goren, Lei Zhong, Oren Ram, Jessica Truelove, Alexander 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. BernsteinAviv Regev, Paul G. Shiels, David B. Lombard, Raul Mostoslavsky

Research output: Contribution to journalArticle

357 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1185-1199
Number of pages15
JournalCell
Volume151
Issue number6
DOIs
Publication statusPublished - Dec 7 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sebastián, C., Zwaans, B. M. M., Silberman, D. M., Gymrek, M., Goren, A., Zhong, L., ... Mostoslavsky, R. (2012). The histone deacetylase SIRT6 Is a tumor suppressor that controls cancer metabolism. Cell, 151(6), 1185-1199. https://doi.org/10.1016/j.cell.2012.10.047