title: Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma.
abstract: 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.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: LaGory
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Wu
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Cullen M
authors.initials: CM
authors.lastname: Taniguchi
authors.affiliation: Duke Center for Genomic and Computational Biology, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27708, USA.
authors.forename: Chien-Kuang Cornelia
authors.initials: CC
authors.lastname: Ding
authors.affiliation: Duke Center for Genomic and Computational Biology, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27708, USA.
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Rie
authors.initials: R
authors.lastname: von Eyben
authors.affiliation: NCI-Designated Cancer Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: NCI-Designated Cancer Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Richardson
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA. Electronic address: giaccia@stanford.edu.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C403671:DELEC1 protein, human; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins