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Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma
Brain metastasis is the most common type of intracranial cancer and is the main cause of cancer-associated mortality. Brain metastasis mainly originates from lung cancer. Using a previously established in vitro brain metastatic model, we found that brain metastatic PC14PE6/LvBr4 cells exhibited high...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756316/ https://www.ncbi.nlm.nih.gov/pubmed/26883469 http://dx.doi.org/10.1038/srep21596 |
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author | Hwang, Su Jin Lee, Hye Won Kim, Hye Ree Lee, Hong Shin, Chang Hoon Yun, Sun-Il Lee, Dong Heon Kim, Duk-Hwan Kim, Kyeong Kyu Joo, Kyeung Min Kim, Hyeon Ho |
author_facet | Hwang, Su Jin Lee, Hye Won Kim, Hye Ree Lee, Hong Shin, Chang Hoon Yun, Sun-Il Lee, Dong Heon Kim, Duk-Hwan Kim, Kyeong Kyu Joo, Kyeung Min Kim, Hyeon Ho |
author_sort | Hwang, Su Jin |
collection | PubMed |
description | Brain metastasis is the most common type of intracranial cancer and is the main cause of cancer-associated mortality. Brain metastasis mainly originates from lung cancer. Using a previously established in vitro brain metastatic model, we found that brain metastatic PC14PE6/LvBr4 cells exhibited higher expression of β-catenin and increased migratory activity than parental PC14PE6 cells. Knockdown of β-catenin dramatically suppressed the motility and invasiveness of PC14PE6/LvBr4 cells, indicating β-catenin is involved in controlling metastatic potential. Since β-catenin protein was increased without a significant change in its mRNA levels, the mechanism underlying increased β-catenin stability was investigated. We found that ubiquitin-specific protease 4 (USP4), recently identified as a β-catenin-specific deubiquitinylating enzyme, was highly expressed in PC14PE6/LvBr4 cells and involved in the increased stability of β-catenin protein. Similar to β-catenin knockdown, USP4-silenced PC14PE6/LvBr4 cells showed decreased migratory and invasive abilities. Moreover, knockdown of both USP4 and β-catenin inhibited clonogenicity and induced mesenchymal-epithelial transition by downregulating ZEB1 in PC14PE6/LvBr4 cells. Using bioluminescence imaging, we found that knockdown of USP4 suppressed brain metastasis in vivo and significantly increased overall survival and brain metastasis-free survival. Taken together, our results indicate that USP4 is a promising therapeutic target for brain metastasis in patients with lung adenocarcinoma. |
format | Online Article Text |
id | pubmed-4756316 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47563162016-02-25 Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma Hwang, Su Jin Lee, Hye Won Kim, Hye Ree Lee, Hong Shin, Chang Hoon Yun, Sun-Il Lee, Dong Heon Kim, Duk-Hwan Kim, Kyeong Kyu Joo, Kyeung Min Kim, Hyeon Ho Sci Rep Article Brain metastasis is the most common type of intracranial cancer and is the main cause of cancer-associated mortality. Brain metastasis mainly originates from lung cancer. Using a previously established in vitro brain metastatic model, we found that brain metastatic PC14PE6/LvBr4 cells exhibited higher expression of β-catenin and increased migratory activity than parental PC14PE6 cells. Knockdown of β-catenin dramatically suppressed the motility and invasiveness of PC14PE6/LvBr4 cells, indicating β-catenin is involved in controlling metastatic potential. Since β-catenin protein was increased without a significant change in its mRNA levels, the mechanism underlying increased β-catenin stability was investigated. We found that ubiquitin-specific protease 4 (USP4), recently identified as a β-catenin-specific deubiquitinylating enzyme, was highly expressed in PC14PE6/LvBr4 cells and involved in the increased stability of β-catenin protein. Similar to β-catenin knockdown, USP4-silenced PC14PE6/LvBr4 cells showed decreased migratory and invasive abilities. Moreover, knockdown of both USP4 and β-catenin inhibited clonogenicity and induced mesenchymal-epithelial transition by downregulating ZEB1 in PC14PE6/LvBr4 cells. Using bioluminescence imaging, we found that knockdown of USP4 suppressed brain metastasis in vivo and significantly increased overall survival and brain metastasis-free survival. Taken together, our results indicate that USP4 is a promising therapeutic target for brain metastasis in patients with lung adenocarcinoma. Nature Publishing Group 2016-02-17 /pmc/articles/PMC4756316/ /pubmed/26883469 http://dx.doi.org/10.1038/srep21596 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Hwang, Su Jin Lee, Hye Won Kim, Hye Ree Lee, Hong Shin, Chang Hoon Yun, Sun-Il Lee, Dong Heon Kim, Duk-Hwan Kim, Kyeong Kyu Joo, Kyeung Min Kim, Hyeon Ho Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma |
title | Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma |
title_full | Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma |
title_fullStr | Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma |
title_full_unstemmed | Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma |
title_short | Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma |
title_sort | ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756316/ https://www.ncbi.nlm.nih.gov/pubmed/26883469 http://dx.doi.org/10.1038/srep21596 |
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