CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
Open Access
- 10 March 2020
- journal article
- research article
- Published by Springer Nature in Signal Transduction and Targeted Therapy
- Vol. 5 (1), 1-13
- https://doi.org/10.1038/s41392-020-0118-x
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.Keywords
Funding Information
- Natural Science Foundation of Tianjin City (17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600, 17JCZDJC36600)
- National Natural Science Foundation of China (81472545, 81472545, 81472545)
This publication has 51 references indexed in Scilit:
- Improved retroviral suicide gene transfer in colon cancer cell lines after cell synchronization with methotrexateJournal of Experimental & Clinical Cancer Research, 2011
- The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAsNature Cell Biology, 2009
- Breaking the chains: structure and function of the deubiquitinasesNature Reviews Molecular Cell Biology, 2009
- Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traitsNature Reviews Cancer, 2009
- The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1Nature Cell Biology, 2008
- δEF1 represses BMP-2-induced differentiation of C2C12 myoblasts into the osteoblast lineageJournal of Biomedical Science, 2007
- NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2Oncogene, 2006
- DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cellsOncogene, 2005
- CYCLIN-DEPENDENT KINASES: Engines, Clocks, and MicroprocessorsAnnual Review of Cell and Developmental Biology, 1997
- Mammalian G1 cyclinsCell, 1993