Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma
We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM usi...
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| author | Jessica Kreienbühl Sakunthip Changkhong Vanessa Orlowski Michaela B. Kirschner Isabelle Opitz Mayura Meerang |
| author_facet | Jessica Kreienbühl Sakunthip Changkhong Vanessa Orlowski Michaela B. Kirschner Isabelle Opitz Mayura Meerang |
| author_sort | Jessica Kreienbühl |
| collection | DOAJ |
| description | We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM using an siRNA approach in PM cell lines (ACC Meso-1 and Mero82) and primary culture. The knockdown of CUL4B and CUL4A resulted in significantly reduced colony formation, increased cell death, and delayed cell proliferation. Furthermore, similar to the effect of CUL4A knockdown, downregulation of CUL4B led to reduced expression of Hippo pathway genes including YAP1, CTGF, and survivin. Interestingly, CUL4B and not CUL4A knockdown reduced TGF-β1 and MMP2 expression, suggesting a unique association of CUL4B with this pathway. However, the treatment of PM cells with exogenous TGF-β1 following CUL4B knockdown did not rescue PM cell growth. We further analyzed ACC Meso-1 xenograft tumor tissues treated with the cullin inhibitor, pevonedistat, which targets protein neddylation, and observed the downregulation of human TGF-β1 and MMP2. In summary, our data suggest that CUL4B overexpression is important for tumor cell growth and survival and may drive PM aggressiveness via the regulation of TGF-β1 expression and, furthermore, reveal a new mechanism of action of pevonedistat. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:21:53Z |
| publishDate | 2023-08-01 |
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| spelling | doaj.art-ca7bd9573a7145f997e2782e06049e322023-11-19T08:16:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171341010.3390/ijms241713410Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural MesotheliomaJessica Kreienbühl0Sakunthip Changkhong1Vanessa Orlowski2Michaela B. Kirschner3Isabelle Opitz4Mayura Meerang5Department of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, SwitzerlandDepartment of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, SwitzerlandDepartment of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, SwitzerlandDepartment of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, SwitzerlandDepartment of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, SwitzerlandDepartment of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, SwitzerlandWe previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM using an siRNA approach in PM cell lines (ACC Meso-1 and Mero82) and primary culture. The knockdown of CUL4B and CUL4A resulted in significantly reduced colony formation, increased cell death, and delayed cell proliferation. Furthermore, similar to the effect of CUL4A knockdown, downregulation of CUL4B led to reduced expression of Hippo pathway genes including YAP1, CTGF, and survivin. Interestingly, CUL4B and not CUL4A knockdown reduced TGF-β1 and MMP2 expression, suggesting a unique association of CUL4B with this pathway. However, the treatment of PM cells with exogenous TGF-β1 following CUL4B knockdown did not rescue PM cell growth. We further analyzed ACC Meso-1 xenograft tumor tissues treated with the cullin inhibitor, pevonedistat, which targets protein neddylation, and observed the downregulation of human TGF-β1 and MMP2. In summary, our data suggest that CUL4B overexpression is important for tumor cell growth and survival and may drive PM aggressiveness via the regulation of TGF-β1 expression and, furthermore, reveal a new mechanism of action of pevonedistat.https://www.mdpi.com/1422-0067/24/17/13410pleural mesotheliomacullin 4Bcullin 4ApevonedistatTGFβMMP2 |
| spellingShingle | Jessica Kreienbühl Sakunthip Changkhong Vanessa Orlowski Michaela B. Kirschner Isabelle Opitz Mayura Meerang Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma International Journal of Molecular Sciences pleural mesothelioma cullin 4B cullin 4A pevonedistat TGFβ MMP2 |
| title | Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma |
| title_full | Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma |
| title_fullStr | Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma |
| title_full_unstemmed | Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma |
| title_short | Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma |
| title_sort | cullin 4b ubiquitin ligase is important for cell survival and regulates tgf β1 expression in pleural mesothelioma |
| topic | pleural mesothelioma cullin 4B cullin 4A pevonedistat TGFβ MMP2 |
| url | https://www.mdpi.com/1422-0067/24/17/13410 |
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