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

Abstract

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.

• Authors: Zhen Zhang, Jianjun Li, Yang Ou, Guang Yang, Kaiyuan Deng, Qiong Wang, Zhaoyang Wang, Wenhao Wang, Quansheng Zhang, Hang Wang, Wei Sun, Peiqing Sun, Shuang Yang
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 5 Issue 1 Pg. 25 (03 11 2020) ISSN: 2059-3635 [Electronic] England
• PMID: 32296027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ZEB1 protein, human
• Zinc Finger E-box-Binding Homeobox 1
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• USP51 protein, human
• Ubiquitin-Specific Proteases

Topics

• Adult
• Animals
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors, genetics)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors, genetics)
• Disease-Free Survival
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Heterografts
• Humans
• Mice
• Middle Aged
• Neoplasm Metastasis
• Neoplasms (genetics, pathology, therapy)
• Ubiquitin-Specific Proteases (genetics)
• Ubiquitination (drug effects, genetics)
• Zinc Finger E-box-Binding Homeobox 1 (genetics)