title: The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism.
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.
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sebastián
authors.forename: Bernadette M M
authors.initials: BM
authors.lastname: Zwaans
authors.forename: Dafne M
authors.initials: DM
authors.lastname: Silberman
authors.forename: Melissa
authors.initials: M
authors.lastname: Gymrek
authors.forename: Alon
authors.initials: A
authors.lastname: Goren
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Oren
authors.initials: O
authors.lastname: Ram
authors.forename: Jessica
authors.initials: J
authors.lastname: Truelove
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Guimaraes
authors.forename: Debra
authors.initials: D
authors.lastname: Toiber
authors.forename: Claudia
authors.initials: C
authors.lastname: Cosentino
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.forename: Alasdair I
authors.initials: AI
authors.lastname: MacDonald
authors.forename: Liane
authors.initials: L
authors.lastname: McGlynn
authors.forename: Fraser
authors.initials: F
authors.lastname: Maxwell
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
authors.forename: Sofia
authors.initials: S
authors.lastname: Giacosa
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.forename: Paul G
authors.initials: PG
authors.lastname: Shiels
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D006019:Glycolysis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; C501860:Sirt6 protein, mouse; C516592:SIRT6 protein, human; D037761:Sirtuins