The E3 ubiquitin ligase RBCK1 promotes the invasion and metastasis of hepatocellular carcinoma by destroying the PPARγ/PGC1α complex.

The disruption of tumour cell metabolism can inhibit tumour metastasis, indicating that aerobic glycolysis is central to tumour development. However, the key factors responsible for mediating aerobic glycolysis in hepatocellular carcinoma (HCC) remain unknown. Here, we observed that RBCK1 expression was significantly upregulated in HCC tissues. Our clinical study revealed that high RBCK1 expression is significantly correlated with poor tumour survival and distant invasion. Functional assays revealed that RBCK1 promotes migration and invasion by enhancing GLUT1-mediated aerobic glycolysis. Furthermore, RBCK1-induced HCC cell migration and aerobic glycolysis via activation of WNT/β-catenin/GLUT1 pathway, which was dependent on the destruction of the PPARγ/PGC1α complex. Mechanistically, RBCK1 promotes PPARγ ubiquitination and degradation, and RBCK1 overexpression enhances the transcriptional activity of WNT/β-catenin, thus to upregulate the expression of GLUT1-mediated aerobic glycolysis in HCC cells. Altogether, our findings identify a mechanism used by HCC cells to survive the nutrient-poor tumour microenvironment and provide insight into the role of RBCK1 in HCC cellular adaptation to metabolic stresses.