The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells
Abstract While an important role for the SUMO protease SENP1 is recognized in multiple solid cancers, its role in renal cell carcinoma (RCC) pathogenesis, particularly the most dominant subtype, clear cell RCC (ccRCC), is poorly understood. Here we show that a combination of high HIF2α and SENP1 exp...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-10-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-022-00440-4 |
| _version_ | 1811198109913448448 |
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| author | Moon Hee Lee Kyung Sung David Beebe Wei Huang Dan Shapiro Shigeki Miyamoto E. Jason Abel |
| author_facet | Moon Hee Lee Kyung Sung David Beebe Wei Huang Dan Shapiro Shigeki Miyamoto E. Jason Abel |
| author_sort | Moon Hee Lee |
| collection | DOAJ |
| description | Abstract While an important role for the SUMO protease SENP1 is recognized in multiple solid cancers, its role in renal cell carcinoma (RCC) pathogenesis, particularly the most dominant subtype, clear cell RCC (ccRCC), is poorly understood. Here we show that a combination of high HIF2α and SENP1 expression in ccRCC samples predicts poor patient survival. Using ccRCC cell models that express high HIF2α but low SENP1, we show that overexpression of SENP1 reduces sumoylation and ubiquitination of HIF2α, increases HIF2α transcriptional activity, and enhances expression of genes associated with cancer cell invasion, stemness and epithelial-mesenchymal transition. Accordingly, ccRCC cells with high HIF2α and SENP1 showed increased invasion and sphere formation in vitro, and local invasion and metastasis in vivo. Finally, SENP1 overexpression caused high HIF2α ccRCC cells to acquire resistance to a clinical mTOR inhibitor, everolimus. These results reveal a combination of high SENP1 and HIF2α expression gives particularly poor prognosis for ccRCC patients and suggest that SENP1 may be an attractive new target for treating metastatic RCC (mRCC). |
| first_indexed | 2024-04-12T01:25:22Z |
| format | Article |
| id | doaj.art-5ee96a81e3a44b89bac3dc2f5661c0ee |
| institution | Directory Open Access Journal |
| issn | 2157-9024 |
| language | English |
| last_indexed | 2024-04-12T01:25:22Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj.art-5ee96a81e3a44b89bac3dc2f5661c0ee2022-12-22T03:53:40ZengNature Publishing GroupOncogenesis2157-90242022-10-011111910.1038/s41389-022-00440-4The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cellsMoon Hee Lee0Kyung Sung1David Beebe2Wei Huang3Dan Shapiro4Shigeki Miyamoto5E. Jason Abel6Department of Urology, University of Wisconsin-MadisonDivision of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, the U.S. FDADepartment of Biomedical Engineering, University of Wisconsin-MadisonUniversity of Wisconsin Carbone Cancer CenterDepartment of Urology, University of Wisconsin-MadisonUniversity of Wisconsin Carbone Cancer CenterDepartment of Urology, University of Wisconsin-MadisonAbstract While an important role for the SUMO protease SENP1 is recognized in multiple solid cancers, its role in renal cell carcinoma (RCC) pathogenesis, particularly the most dominant subtype, clear cell RCC (ccRCC), is poorly understood. Here we show that a combination of high HIF2α and SENP1 expression in ccRCC samples predicts poor patient survival. Using ccRCC cell models that express high HIF2α but low SENP1, we show that overexpression of SENP1 reduces sumoylation and ubiquitination of HIF2α, increases HIF2α transcriptional activity, and enhances expression of genes associated with cancer cell invasion, stemness and epithelial-mesenchymal transition. Accordingly, ccRCC cells with high HIF2α and SENP1 showed increased invasion and sphere formation in vitro, and local invasion and metastasis in vivo. Finally, SENP1 overexpression caused high HIF2α ccRCC cells to acquire resistance to a clinical mTOR inhibitor, everolimus. These results reveal a combination of high SENP1 and HIF2α expression gives particularly poor prognosis for ccRCC patients and suggest that SENP1 may be an attractive new target for treating metastatic RCC (mRCC).https://doi.org/10.1038/s41389-022-00440-4 |
| spellingShingle | Moon Hee Lee Kyung Sung David Beebe Wei Huang Dan Shapiro Shigeki Miyamoto E. Jason Abel The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells Oncogenesis |
| title | The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells |
| title_full | The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells |
| title_fullStr | The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells |
| title_full_unstemmed | The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells |
| title_short | The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells |
| title_sort | sumo protease senp1 promotes aggressive behaviors of high hif2α expressing renal cell carcinoma cells |
| url | https://doi.org/10.1038/s41389-022-00440-4 |
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