RNF6 facilitates metastasis and radioresistance in hepatocellular carcinoma through ubiquitination of FoxA1.

Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin Ligase, functions as a potential tumor promoter in several caners. However, the function and clinical significance of RNF6 in hepatocellular carcinoma (HCC) remains unclear. Here, we found that high RNF6 expression was detected frequently in primary HCC tissues, and was closely associated with malignant phenotype and shorter survival among the HCC patients. Multivariate analyses also revealed that RNF6 overexpression was independent prognostic factors for poor outcome of patients with HCC. Further, RNF6 knockdown notably inhibited the metastasis abilities of HCC in vivo and in vitro. RNF6 silence also suppressed the epithelial-mesenchymal transition (EMT) and radioresistance in HCC. Mechanistically, our results demonstrated that RNF6 directly bound and ubiquitylated Forkhead box protein A1 (FoxA1), an important transcriptional repressor of EMT process. Additionally, our data shown that the oncogenic effect of RNF6 in HCC is partially dependent on FoxA1 degradation. Collectively, our data suggest that RNF6 plays a crucial oncogenic role in HCC tumorigenesis, and we provide a novel evidence that RNF6 may be serve as a prognostic and therapeutic target for HCC progression.