CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
Identifieur interne : 000196 ( Main/Merge ); précédent : 000195; suivant : 000197CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
Auteurs : Zhen Zhang [République populaire de Chine] ; Jianjun Li [République populaire de Chine] ; Yang Ou [République populaire de Chine] ; Guang Yang [République populaire de Chine] ; Kaiyuan Deng [République populaire de Chine] ; Qiong Wang [République populaire de Chine] ; Zhaoyang Wang [République populaire de Chine] ; Wenhao Wang [République populaire de Chine] ; Quansheng Zhang [République populaire de Chine] ; Hang Wang [République populaire de Chine] ; Wei Sun [République populaire de Chine] ; Peiqing Sun [États-Unis] ; Shuang Yang [République populaire de Chine]Source :
- Signal Transduction and Targeted Therapy [ 2095-9907 ] ; 2020.
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
Url:
DOI: 10.1038/s41392-020-0118-x
PubMed: 32195004
PubMed Central: 7064488
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<series><title level="j">Signal Transduction and Targeted Therapy</title>
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<front><div type="abstract" xml:lang="en"><p id="Par1">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 <italic>p</italic>
-RB (an indicator of CDK4/6 activity), <italic>p</italic>
-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of <italic>p</italic>
-RB, <italic>p</italic>
-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.</p>
</div>
</front>
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</author>
<author><name sortKey="Swanton, C" uniqKey="Swanton C">C Swanton</name>
</author>
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