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PMID: 21397863 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.

Cancer cell ·Vol. 19 ·No. 3 ·2011-03-08 ·Pages 416-28

Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, Pandolfi PP, Haigis MC

Abstract

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.

MeSH Terms
Animals Cell Hypoxia Cell Line, Tumor Cells, Cultured Fibroblasts/cytology,metabolism Gene Expression Glucose/metabolism Glycolysis HEK293 Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Immunoblotting Male Metabolomics/methods Mice Mice, 129 Strain Mice, Knockout Mice, Nude Neoplasms/genetics,metabolism,pathology Protein Stability Reactive Oxygen Species/metabolism Reverse Transcriptase Polymerase Chain Reaction Sirtuin 3/genetics,metabolism Transplantation, Heterologous
Chemicals
Hypoxia-Inducible Factor 1, alpha Subunit Reactive Oxygen Species Sirt3 protein, mouse SIRT3 protein, human Sirtuin 3 Glucose
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Finley Lydia W S
Department of Pathology, The Paul F. Glenn Labs for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.
Carracedo Arkaitz
Lee Jaewon
Souza Amanda
Egia Ainara
Zhang Jiangwen
Teruya-Feldstein Julie
Moreira Paula I
Cardoso Sandra M
Clish Clary B
Pandolfi Pier Paolo
Haigis Marcia C
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2011.02.014
Published
2011-03-08
Pages
416-28
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3065720
Subset
IM
Grants
NIA NIH HHS · R01 AG032375 · United States
NIA NIH HHS · R01 AG032375-02 · United States
NIA NIH HHS · AG032375 · United States
Corrections
CommentIn
PMID: 21397853
External Links
PubMed source DOI: 10.1016/j.ccr.2011.02.014 PMC Full Text View journal details
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