CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
Identifieur interne : 000196 ( an2020/Analysis ); 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
Affiliations:
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Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Zhaoyang" sort="Wang, Zhaoyang" uniqKey="Wang Z" first="Zhaoyang" last="Wang">Zhaoyang Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Wenhao" sort="Wang, Wenhao" uniqKey="Wang W" first="Wenhao" last="Wang">Wenhao Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Quansheng" sort="Zhang, Quansheng" uniqKey="Zhang Q" first="Quansheng" last="Zhang">Quansheng Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0605 6814</institution-id><institution-id institution-id-type="GRID">grid.417024.4</institution-id><institution>Tianjin Key Laboratory of Organ Transplantation,</institution><institution>Tianjin First Center Hospital,</institution></institution-wrap>Tianjin, 300192 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Hang" sort="Wang, Hang" uniqKey="Wang H" first="Hang" last="Wang">Hang Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Sun, Wei" sort="Sun, Wei" uniqKey="Sun W" first="Wei" last="Sun">Wei Sun</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Sun, Peiqing" sort="Sun, Peiqing" uniqKey="Sun P" first="Peiqing" last="Sun">Peiqing Sun</name><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2185 3318</institution-id><institution-id institution-id-type="GRID">grid.241167.7</institution-id><institution>Department of Cancer Biology,</institution><institution>Wake Forest University School of Medicine,</institution></institution-wrap>Winston-Salem, NC 27157 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Winston-Salem</wicri:cityArea></affiliation></author><author><name sortKey="Yang, Shuang" sort="Yang, Shuang" uniqKey="Yang S" first="Shuang" last="Yang">Shuang Yang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author></analytic><series><title level="j">Signal Transduction and Targeted Therapy</title><idno type="ISSN">2095-9907</idno><idno type="eISSN">2059-3635</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Turajlic, S" uniqKey="Turajlic S">S Turajlic</name></author><author><name sortKey="Swanton, C" uniqKey="Swanton C">C Swanton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nan, Xiang" uniqKey="Nan X">Xiang Nan</name></author><author><name sortKey="Wang, Jiang" uniqKey="Wang J">Jiang Wang</name></author><author><name sortKey="Liu, Haowen Nikola" uniqKey="Liu H">Haowen Nikola Liu</name></author><author><name sortKey="Wong, Stephen T C" uniqKey="Wong S">Stephen T.C. 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Jianjun" sort="Li, Jianjun" uniqKey="Li J" first="Jianjun" last="Li">Jianjun Li</name><name sortKey="Ou, Yang" sort="Ou, Yang" uniqKey="Ou Y" first="Yang" last="Ou">Yang Ou</name><name sortKey="Sun, Wei" sort="Sun, Wei" uniqKey="Sun W" first="Wei" last="Sun">Wei Sun</name><name sortKey="Wang, Hang" sort="Wang, Hang" uniqKey="Wang H" first="Hang" last="Wang">Hang Wang</name><name sortKey="Wang, Qiong" sort="Wang, Qiong" uniqKey="Wang Q" first="Qiong" last="Wang">Qiong Wang</name><name sortKey="Wang, Wenhao" sort="Wang, Wenhao" uniqKey="Wang W" first="Wenhao" last="Wang">Wenhao Wang</name><name sortKey="Wang, Zhaoyang" sort="Wang, Zhaoyang" uniqKey="Wang Z" first="Zhaoyang" last="Wang">Zhaoyang Wang</name><name sortKey="Yang, Guang" sort="Yang, Guang" uniqKey="Yang G" first="Guang" last="Yang">Guang Yang</name><name sortKey="Yang, Shuang" sort="Yang, Shuang" uniqKey="Yang S" first="Shuang" last="Yang">Shuang Yang</name><name sortKey="Zhang, Quansheng" sort="Zhang, Quansheng" uniqKey="Zhang Q" first="Quansheng" last="Zhang">Quansheng Zhang</name></country><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Sun, Peiqing" sort="Sun, Peiqing" uniqKey="Sun P" first="Peiqing" last="Sun">Peiqing Sun</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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