The E3 Ubiquitin Ligase RBCK1 Promotes The Invasion and Metastasis of Hepatocellular Carcinoma By Destroying The PPARγ/PGC1α Complex

Background: 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. Methods: This study investigated the function and clinical significance of RBCK1 protein expression in HCC. We analyzed RBCK1 expression from the TCGA-LIHC dataset and surgical specimens of 216 HCC patients. The correlation between the clinical characteristics and prognosis was also determined. Furthermore, over-expression and knockdown experiments of RBCK1 were developed to explore their effects on HCC cell migration, invasion and aerobic glycolysis. Moreover, a molecular mechanism of RBCK1 promotes HCC metastasis was explored.Results: Here, we observed that RBCK1 expression was significantly upregulated in HCC tissues. Our clinical study showed that high RBCK1 expression significantly correlated with poor tumour survival and distant invasion. Functional assays using HCC cells revealed that RBCK1 promoted migration and invasion by enhancing the Warburg effect, and that GLUT1 was critical for RBCK1-mediated aerobic glycolysis. Furthermore, RBCK1-mediated regulation of WNT/β-catenin/GLUT1 pathway-induced HCC cell migration and aerobic glycolysis was dependent on the destruction of the PPARγ/PGC1α complex. Mechanistically, RBCK1 promoted PPARγ ubiquitination and degradation, causing RBCK1 overexpression to enhance the transcriptional activity of WNT/β-catenin. This consequently upregulated the expression of GLUT1-mediated aerobic glycolysis in HCC cells, promoting tumour cell metastasis and invasion.Conclusion: Altogether, our findings identify a mechanism used by HCC cells to survive the nutrient-poor tumour microenvironment and also provide insight into the role of RBCK1 in HCC cell adaptation to metabolic stresses.