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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.

Original publication

DOI

10.1016/j.celrep.2015.06.006

Type

Journal article

Journal

Cell Rep

Publication Date

07/07/2015

Volume

12

Pages

116 - 127

Keywords

Animals, Carcinogenesis, Carcinoma, Renal Cell, Cell Line, Tumor, Humans, Mice, Mitochondria, Oxidative Phosphorylation, Oxidative Stress, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Transcription Factors, Tumor Suppressor Proteins