Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein
Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life‐threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor‐β (TGF‐β) is closely associated with advanced HCC metastasis. However, the...
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doaj-827e28fc63ba47519fc60a8543d9f7ac2020-11-25T03:54:40ZengWileyMolecular Oncology1574-78911878-02612020-01-0114119721010.1002/1878-0261.12596Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 proteinTao Yuan0Zibo Chen1Fangjie Yan2Meijia Qian3Hong Luo4Song Ye5Ji Cao6Meidan Ying7Xiaoyang Dai8Renhua Gai9Bo Yang10Qiaojun He11Hong Zhu12Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaCancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital Hangzhou ChinaDepartment of Hepatobiliary and Pancreatic Surgery the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaZhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University Hangzhou ChinaHepatocellular carcinoma (HCC) has emerged as one of the most prevalent life‐threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor‐β (TGF‐β) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF‐β pathway remains elusive. In this study, using a functional screen of USPs siRNA library, we identified ubiquitin‐specific proteases USP10 as a deubiquitinating enzyme (DUB) that sustains the protein level of Smad4 and activates TGF‐β signaling. Further analysis showed that USP10 directly interacts with Smad4 and stabilizes it through the cleavage of its proteolytic ubiquitination, thus promoting HCC metastasis. The suppression of USP10 by either shRNAs or catalytic inhibitor Spautin‐1 significantly inhibited the migration of HCC cells, whereas the reconstitution of Smad4 was able to efficiently rescue this defect. Overall, our study not only uncovers the regulatory effect of USP10 on the protein abundance of Smad4, but also indicates that USP10 could be regarded as a potential intervention target for the metastatic HCC in Smad4‐positive patients.https://doi.org/10.1002/1878-0261.12596deubiquitinating enzymehepatocellular carcinomametastasisSmad4USP10 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tao Yuan Zibo Chen Fangjie Yan Meijia Qian Hong Luo Song Ye Ji Cao Meidan Ying Xiaoyang Dai Renhua Gai Bo Yang Qiaojun He Hong Zhu |
spellingShingle |
Tao Yuan Zibo Chen Fangjie Yan Meijia Qian Hong Luo Song Ye Ji Cao Meidan Ying Xiaoyang Dai Renhua Gai Bo Yang Qiaojun He Hong Zhu Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein Molecular Oncology deubiquitinating enzyme hepatocellular carcinoma metastasis Smad4 USP10 |
author_facet |
Tao Yuan Zibo Chen Fangjie Yan Meijia Qian Hong Luo Song Ye Ji Cao Meidan Ying Xiaoyang Dai Renhua Gai Bo Yang Qiaojun He Hong Zhu |
author_sort |
Tao Yuan |
title |
Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein |
title_short |
Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein |
title_full |
Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein |
title_fullStr |
Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein |
title_full_unstemmed |
Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein |
title_sort |
deubiquitinating enzyme usp10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing smad4 protein |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2020-01-01 |
description |
Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life‐threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor‐β (TGF‐β) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF‐β pathway remains elusive. In this study, using a functional screen of USPs siRNA library, we identified ubiquitin‐specific proteases USP10 as a deubiquitinating enzyme (DUB) that sustains the protein level of Smad4 and activates TGF‐β signaling. Further analysis showed that USP10 directly interacts with Smad4 and stabilizes it through the cleavage of its proteolytic ubiquitination, thus promoting HCC metastasis. The suppression of USP10 by either shRNAs or catalytic inhibitor Spautin‐1 significantly inhibited the migration of HCC cells, whereas the reconstitution of Smad4 was able to efficiently rescue this defect. Overall, our study not only uncovers the regulatory effect of USP10 on the protein abundance of Smad4, but also indicates that USP10 could be regarded as a potential intervention target for the metastatic HCC in Smad4‐positive patients. |
topic |
deubiquitinating enzyme hepatocellular carcinoma metastasis Smad4 USP10 |
url |
https://doi.org/10.1002/1878-0261.12596 |
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