Cited by 664Sirtuins and Resveratrol in MedicineCancer, Hypoxia, and MetabolismMetabolism, Diabetes, and Cancer

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

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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·2012·Cell

DOI 10.1016/j.cell.2012.10.047PMC PMC3526953

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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.

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Authors: Sebastián, C., Zwaans, B. M. M., Silberman, D. M., Gymrek, M., Goren, A., Zhong, L., Ram, O., Truelove, J., Guimaraes, A. R., Toiber, D., Cosentino, C., Greenson, J. K., MacDonald, A. I., McGlynn, L., Maxwell, F., Edwards, J., Giacosa, S., Guccione, E., Weissleder, R., Bernstein, B. E., Regev, A., Shiels, P. G., Lombard, D. B., & Mostoslavsky, R.
Affiliations: Harvard University (US)
University of Michigan (US)
Harvard–MIT Division of Health Sciences and Technology (US)
Broad Institute (US)
Massachusetts General Hospital (US)
University of Glasgow (GB)
Institute of Molecular and Cell Biology (SG)
Corresponding author: Lombard, David B.
ORCID: Sebastián, Carlos
Zwaans, Bernadette M.M.
Silberman, Dafne M.
Gymrek, Melissa
Goren, Alon
Zhong, Lei
Ram, Oren
Toiber, Debra
Cosentino, Claudia
Greenson, Joel K.
Edwards, Joanne
Guccione, Ernesto
Weissleder, Ralph
Bernstein, Bradley E.
Regev, Aviv
Shiels, Paul G.
Lombard, David B.
Venue: Cell
Publisher: Elsevier BV
Published: 2012-12
Volume: 151
Issue: 6
Pages: 1185-1199
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2012.10.047
PMC: PMC3526953
OpenAlex: W2138062757
Cited by: 660
References: 65
Citations by year: 2026: 26 · 2025: 23 · 2024: 27 · 2023: 36 · 2022: 51 · 2021: 52 · 2020: 52 · 2019: 47 · 2018: 53 · 2017: 53 · 2016: 63 · 2015: 59 · 2014: 54 · 2013: 58 · 2012: 4
FWCI: 27.61
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
CONICET Digital (CONICET) (submittedVersion, cc-by-nc-nd)
Elsevier eBooks
Funders: Howard Hughes Medical Institute
National Institute on Aging (P30AG013283)
National Human Genome Research Institute (P50HG006193)
National Cancer Institute (R01CA175727)
National Institute of General Medical Sciences (GM093072-01, GM101171, R01GM093072, R01GM101171)
National Institute of Diabetes and Digestive and Kidney Diseases (DK088190-01A1, R01DK088190)
National Institute of Biomedical Imaging and Bioengineering (K08EB012859)
Topics: Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: SIRT6, histone deacetylase, tumor suppressor, cancer metabolism, aerobic glycolysis, Warburg effect, tumor growth, prognosis, conditional knockout
MeSH terms: Animals, Fibroblasts, Glycolysis, Humans, Mice, Nude, Neoplasm Transplantation, Neoplasms, Transcription, Genetic, Transplantation, Heterologous, Down-Regulation, Proto-Oncogene Proteins c-myc, Mice, SCID, Tumor Suppressor Proteins, Sirtuins, Cell Proliferation, Mice, Gene Knockout Techniques

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

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