CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism

Tumor metastasis is the most common cause of cancer-related deaths,yet it remains poorly understood.The transcription factor zinc-finger E-box binding homeobox 1(ZEB1)is involved in the epithelial-to-mesenchymal transition(EMT)and plays a pivotal role in tumor metastasis.However,the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown.Herein,we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo.Mechanistically,we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6.The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1.Moreover,we found a strong positive correlation between the expression of p-RB(an indicator of CDK4/6 activity),p-USP51 and ZEB1 in metastatic human breast cancer samples.Notably,the high expression of p-RB,p-USP51,and ZEB1 was significantly correlated with a poor clinical outcome.Taken together,our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.