In this study, for the first time, we showed that down-regulation of SIK1 was inhibited in HCC cell lines with RNF2 knockdown, and that exogenous RNF2 decreased the stability of SIK1, which indicates that RNF2-mediated SIK1 degradation is dependent on the proteasome pathway. This evidence concerns the gene SIK1 and hepatocellular carcinoma.