Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma

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-1 alpha, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1 alpha suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1 alpha expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1 alpha exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1 alpha expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1 alpha recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1 alpha expression as a therapeutic modality for the treatment of ccRCC.