CDK4/6-USP51 axis regulates lung adenocarcinoma metastasis through ZEB1

USP51 is a member of the deubiquitinase (DUB) family that participates in many pathophysiological processes. However, the aberrant expression and biological function of USP51 in cancer progression remain largely unclear. In this study, we demonstrated that USP51 is overexpressed in metastatic human lung adenocarcinoma and patients with high USP51 expression in their tumors have shorter overall survival than those with low expression of USP51. Moreover, we showed that USP51 promotes tumor metastasis and invasion through regulating ZEB1, which is a key transcriptional factor that induces the malignant progression of lung adenocarcinoma. In terms of molecular mechanism, USP51 is phosphorylated and activated by CDK4/6, thus resulting in the deubiquitination and stabilization of ZEB1 protein. Of note, we also confirmed that the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 are significantly positively correlated in human lung adenocarcinoma samples. In conclusion, these findings revealed that the CDK4/6-USP51-ZEB1 signaling pathway is a driver of lung adenocarcinoma metastasis, which could be a potential therapeutic strategy for the treatment of malignant tumors.