Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma
Edward L. LaGory,
Colleen Wu,
Cullen M. Taniguchi,
Chien-Kuang Cornelia Ding,
Jen-Tsan Chi,
Rie von Eyben,
David A. Scott,
Adam D. Richardson,
Amato J. Giaccia
Affiliations
Edward L. LaGory
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
Colleen Wu
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
Cullen M. Taniguchi
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
Chien-Kuang Cornelia Ding
Duke Center for Genomic and Computational Biology, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27708, USA
Jen-Tsan Chi
Duke Center for Genomic and Computational Biology, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27708, USA
Rie von Eyben
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
David A. Scott
NCI-Designated Cancer Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
Adam D. Richardson
NCI-Designated Cancer Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
Amato J. Giaccia
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1α, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1α suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1α expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1α exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1α expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1α recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1α expression as a therapeutic modality for the treatment of ccRCC.
