PGC1α suppresses metastasis of HCC by inhibiting Warburg effect via PPARγ‐dependent WNT/β‐catenin/PDK1 axis

Peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha (PGC1alpha) is a key regulator of mitochondrial biogenesis and respiration. PGC1alpha is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we observed that PGC1alpha was downregulated in human HCC. A clinical study showed that the low levels of PGC1alpha expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1alpha inhibited the migration and invasion of HCC cells both in vitro experiment and in vivo mouse model. Mechanistically, PGC1alpha suppressed Warburg effect through the downregulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by WNT/beta-catenin pathway, and the inhibition of WNT/beta-catenin pathway was induced by the activation of PPARgamma. Conclusion: Low levels of PGC1alpha expression indicate a poor prognosis for HCC patients. PGC1alpha suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating WNT/beta-catenin/PDK1 axis, which depends on PPARgamma. PGC1alpha is a potential factor for predicting prognosis and therapeutic target for HCC patients.