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PMID: 32296027 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

Signal transduction and targeted therapy ·Vol. 5 ·No. 1 ·2020-00-11 ·Pages 25

Zhang Z, Li J, Ou Y, Yang G, Deng K, Wang Q, Wang Z, Wang W, Zhang Q, Wang H, Sun W, Sun P, Yang S

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.

MeSH Terms
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
Chemicals
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
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Zhang Zhen
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Li Jianjun
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Ou Yang
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Yang Guang
College of Pharmacy, Nankai University, Tianjin, 300071, China.
Deng Kaiyuan
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Wang Qiong
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Wang Zhaoyang
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Wang Wenhao
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Zhang Quansheng
Tianjin Key Laboratory of Organ Transplantation, Tianjin First Center Hospital, Tianjin, 300192, China.
Wang Hang
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Sun Wei
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.
Sun Peiqing
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
Yang Shuang
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China. yangshuang@nankai.edu.cn.
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Article Info
Journal
Signal transduction and targeted therapy
Abbr.
Signal Transduct Target Ther
ISSN
2059-3635
DOI
10.1038/s41392-020-0118-x
Email
yangshuang@nankai.edu.cn
Published
2020-00-11
Epub
2020-00-11
Pages
25
Language
English
Region
England
NLM ID
101676423
PMCID
PMC7064488
Corrections
ErratumIn
PMID: 34145216
External Links
PubMed source DOI: 10.1038/s41392-020-0118-x PMC Full Text View journal details
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