TY - JOUR
T1 - SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization
AU - Finley, Lydia W.S.
AU - Carracedo, Arkaitz
AU - Lee, Jaewon
AU - Souza, Amanda
AU - Egia, Ainara
AU - Zhang, Jiangwen
AU - Teruya-Feldstein, Julie
AU - Moreira, Paula I.
AU - Cardoso, Sandra M.
AU - Clish, Clary B.
AU - Pandolfi, Pier Paolo
AU - Haigis, Marcia C.
N1 - Funding Information:
We thank Fred Alt for the SIRT3 KO mice. We thank Elaine Lunsford and the Longwood SAIF for the PET/CT imaging and analysis, Kristin Waraska and the Harvard Biopolymers Facility for running the TaqMan assays, Kelly Dakin and Bruce Yankner for use of their hypoxic incubator, Natalie German and Maren Shapiro for technical assistance, Ditte Lee for help with mouse work, and Maria Jiao in the Laboratory of Comparative Pathology, Sloan Kettering Institute, for immunohistochemical technical assistance. We thank Kevin Haigis, Carla Kim, and Karen Cichowski for critical reading of the manuscript, and David Gius, Sandra Ryeom, Gaelle Laurent, Lenny Guarente, and Eric Bell for helpful discussion. L.W.S.F. is supported by a National Science Foundation graduate research fellowship. A.C. is supported by the Ramón y Cajal award. M.C.H. is supported in part by NIH grant AG032375, and funding from the Paul F. Glenn Foundation, the Alexander and Margaret Stewart Trust, and the Muscular Dystrophy Association.
PY - 2011/3/8
Y1 - 2011/3/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79952501323&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2011.02.014
DO - 10.1016/j.ccr.2011.02.014
M3 - Article
C2 - 21397863
AN - SCOPUS:79952501323
SN - 1535-6108
VL - 19
SP - 416
EP - 428
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -