Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis
Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered r...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
|
| Series: | Cancer Biology & Therapy |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15384047.2022.2054242 |
| _version_ | 1797404053891710976 |
|---|---|
| author | Zibo Chen Lin Zheng Yulong Chen Xiuxia Liu Masanori Kawakami Lisa Maria Mustachio Jason Roszik Katherine V. Ferry-Galow Ralph E. Parchment Xin Liu Thorkell Andresson Gerard Duncan Jonathan M. Kurie Jaime Rodriguez-Canales Xi Liu Ethan Dmitrovsky |
| author_facet | Zibo Chen Lin Zheng Yulong Chen Xiuxia Liu Masanori Kawakami Lisa Maria Mustachio Jason Roszik Katherine V. Ferry-Galow Ralph E. Parchment Xin Liu Thorkell Andresson Gerard Duncan Jonathan M. Kurie Jaime Rodriguez-Canales Xi Liu Ethan Dmitrovsky |
| author_sort | Zibo Chen |
| collection | DOAJ |
| description | Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced lung cancer growth, wound-healing, migration, and invasion versus controls (P < .001) and markedly decreased murine lung cancer metastases (P < .001). Reverse Phase Protein Arrays (RPPAs) in shRNA knock-down lung cancer cells showed that 14-3-3ζ protein was regulated by loss of USP18. ISG15 complexed with 14-3-3ζ protein reducing its stability. Survival in lung adenocarcinomas (P < .0015) and other cancers was linked to elevated 14-3-3ζ expression as assessed by The Cancer Genome Atlas (TCGA). The findings were confirmed and extended using 14-3-3ζ immunohistochemical assays of human lung cancer arrays and syngeneic murine lung cancer metastasis models. A direct 14-3-3ζ role in controlling lung cancer metastasis came from engineered 14-3-3ζ knock-down in lung cancer cell lines and 14-3-3ζ rescue experiments that reversed migration and invasion inhibition. Findings presented here revealed that USP18 controlled metastasis by regulating 14-3-3ζ expression. These data provide a strong rationale for developing a USP18 inhibitor to combat metastases. |
| first_indexed | 2024-03-09T02:47:33Z |
| format | Article |
| id | doaj.art-89c6b8309f354ba2877fae72139376be |
| institution | Directory Open Access Journal |
| issn | 1538-4047 1555-8576 |
| language | English |
| last_indexed | 2024-03-09T02:47:33Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj.art-89c6b8309f354ba2877fae72139376be2023-12-05T15:58:13ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762022-12-0123126528010.1080/15384047.2022.20542422054242Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasisZibo Chen0Lin Zheng1Yulong Chen2Xiuxia Liu3Masanori Kawakami4Lisa Maria Mustachio5Jason Roszik6Katherine V. Ferry-Galow7Ralph E. Parchment8Xin Liu9Thorkell Andresson10Gerard Duncan11Jonathan M. Kurie12Jaime Rodriguez-Canales13Xi Liu14Ethan Dmitrovsky15The University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterFrederick National Laboratory for Cancer ResearchThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterFrederick National Laboratory for Cancer ResearchFrederick National Laboratory for Cancer ResearchThe University of Texas MD Anderson Cancer CenterFrederick National Laboratory for Cancer ResearchFrederick National Laboratory for Cancer ResearchThe University of Texas MD Anderson Cancer CenterAstraZenecaThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterCancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced lung cancer growth, wound-healing, migration, and invasion versus controls (P < .001) and markedly decreased murine lung cancer metastases (P < .001). Reverse Phase Protein Arrays (RPPAs) in shRNA knock-down lung cancer cells showed that 14-3-3ζ protein was regulated by loss of USP18. ISG15 complexed with 14-3-3ζ protein reducing its stability. Survival in lung adenocarcinomas (P < .0015) and other cancers was linked to elevated 14-3-3ζ expression as assessed by The Cancer Genome Atlas (TCGA). The findings were confirmed and extended using 14-3-3ζ immunohistochemical assays of human lung cancer arrays and syngeneic murine lung cancer metastasis models. A direct 14-3-3ζ role in controlling lung cancer metastasis came from engineered 14-3-3ζ knock-down in lung cancer cell lines and 14-3-3ζ rescue experiments that reversed migration and invasion inhibition. Findings presented here revealed that USP18 controlled metastasis by regulating 14-3-3ζ expression. These data provide a strong rationale for developing a USP18 inhibitor to combat metastases.http://dx.doi.org/10.1080/15384047.2022.2054242deubiquitinaseusp1814-3-3ζlung cancer and metastasis |
| spellingShingle | Zibo Chen Lin Zheng Yulong Chen Xiuxia Liu Masanori Kawakami Lisa Maria Mustachio Jason Roszik Katherine V. Ferry-Galow Ralph E. Parchment Xin Liu Thorkell Andresson Gerard Duncan Jonathan M. Kurie Jaime Rodriguez-Canales Xi Liu Ethan Dmitrovsky Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis Cancer Biology & Therapy deubiquitinase usp18 14-3-3ζ lung cancer and metastasis |
| title | Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis |
| title_full | Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis |
| title_fullStr | Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis |
| title_full_unstemmed | Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis |
| title_short | Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis |
| title_sort | loss of ubiquitin specific peptidase 18 destabilizes 14 3 3ζ protein and represses lung cancer metastasis |
| topic | deubiquitinase usp18 14-3-3ζ lung cancer and metastasis |
| url | http://dx.doi.org/10.1080/15384047.2022.2054242 |
| work_keys_str_mv | AT zibochen lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT linzheng lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT yulongchen lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT xiuxialiu lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT masanorikawakami lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT lisamariamustachio lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT jasonroszik lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT katherinevferrygalow lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT ralpheparchment lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT xinliu lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT thorkellandresson lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT gerardduncan lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT jonathanmkurie lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT jaimerodriguezcanales lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT xiliu lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis AT ethandmitrovsky lossofubiquitinspecificpeptidase18destabilizes1433zproteinandrepresseslungcancermetastasis |