THE HISTONE DEACETYLASE SIRT6 IS A NOVEL TUMOR SUPPRESSOR THAT CONTROLS CANCER METABOLISM

By C. Sebastián, Bernardette M. M. Zwaans, D. M. Silberman, M. Gymrek, Amir Goren, Lei Zhong, Oren Ram, J. Truelove, Alexander R. Guimaraes, D. Toiber and 14 more. Cell, 2012

649 citations recorded by the source corpus.

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 novel tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, while transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. 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 novel regulator of ribosome metabolism by co-repressing 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.

View Paper: https://www.semanticscholar.org/paper/2a06bfdfb305f15781df4e2b4a9a7a35c45efac2

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Citations in the corpus

SIRT1 and other sirtuins in Metabolism (2013, background): “SIRT1, SIRT6 and SIRT7 are localized in the nucleus, where they function to deacetylate histones thereby influencing gene expression epigenetically [14].”
Influence of Metabolism on Epigenetics and Disease (2013, unknown): “In this regard, it is particularly intriguing that the battery of SIRT6 target genes (Sebastián et al., 2012) has been reported to overlap significantly with genes codependent on the c-Myc oncoprotein and the SAGA/GCN5 histone acetylase complex (Cai et.”
Histone Modifications and Cancer. (2016, background): “SIRT3, and perhaps also SIRT6, have been identified as tumor suppressors that regulate glycolysis in tumor cell (Haigis et al. 2012; Sebastian et al. 2012), with reduced expression in human breast cancer tissue versus normal.”
The world of protein acetylation. (2016, background): “found that decreased levels of SIRT6 leads to upregulation of targets of its repressive activity, namely Myc and HIF1, leading to increased cell division and glycolysis, both hallmarks of cancer [431].”