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Cancer Cell DOI:10.1016/j.ccr.2011.02.014

SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.

Publication TypeJournal Article
Year of Publication2011
AuthorsFinley, LWS, Carracedo, A, Lee, J, Souza, A, Egia, A, Zhang, J, Teruya-Feldstein, J, Moreira, PI, Cardoso, SM, Clish, CB, Pandolfi, PPaolo, Haigis, MC
JournalCancer Cell
Date Published2011 Mar 08
KeywordsAnimals, Cell Hypoxia, Cell Line, Tumor, Cells, Cultured, Fibroblasts, Gene Expression, Glucose, Glycolysis, HEK293 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Male, Metabolomics, Mice, Mice, 129 Strain, Mice, Knockout, Mice, Nude, Neoplasms, Protein Stability, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, Sirtuin 3, Transplantation, Heterologous

Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates required for biomass generation. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1α stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1α target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.


Alternate JournalCancer Cell
PubMed ID21397863
PubMed Central IDPMC3065720
Grant ListR01 AG032375 / AG / NIA NIH HHS / United States
R01 AG032375-02 / AG / NIA NIH HHS / United States
AG032375 / AG / NIA NIH HHS / United States