USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer
Abstract The emerging role of ubiquitin-specific peptidase 21 (USP21) in stabilizing Fra-1 (FOSL1) highlights its involvement in promoting colorectal cancer (CRC) metastasis. Additionally, a reciprocal link between EGFR signaling and Fra-1 activation has been identified, mediated through matrix meta...
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| Format: | Article |
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Nature Publishing Group
2024-12-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-024-02255-1 |
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| _version_ | 1850131488650035200 |
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| author | Ji Hye Shin Mi-Jeong Kim Ji Young Kim Bongkum Choi Yeeun Kang Seo Hyun Kim Ha-Jeong Lee Dohee Kwon Yong Beom Cho Kyeong Kyu Kim Eunyoung Chun Ki-Young Lee |
| author_facet | Ji Hye Shin Mi-Jeong Kim Ji Young Kim Bongkum Choi Yeeun Kang Seo Hyun Kim Ha-Jeong Lee Dohee Kwon Yong Beom Cho Kyeong Kyu Kim Eunyoung Chun Ki-Young Lee |
| author_sort | Ji Hye Shin |
| collection | DOAJ |
| description | Abstract The emerging role of ubiquitin-specific peptidase 21 (USP21) in stabilizing Fra-1 (FOSL1) highlights its involvement in promoting colorectal cancer (CRC) metastasis. Additionally, a reciprocal link between EGFR signaling and Fra-1 activation has been identified, mediated through matrix metalloproteinases (MMPs). However, the functional implications of the USP21-EGFR signaling axis in metastatic CRC (mCRC) are not fully understood. To investigate the clinical correlation between USP21 and EGFR expression, RNA-Seq data from tumor tissues (n = 27) and matched normal tissues (n = 27) of 27 mCRC patients were analyzed. Functional studies were performed, including the use of CRISPR/Cas9 to generate USP21-knockout (USP21-KO) CRC cells, in vitro assays for cancer progression and tumor formation, in vivo xenograft assays in NSG mice. Additionally, the therapeutic effect of the USP21 inhibitor, BAY-805, was evaluated. We found that elevated levels of USP21 and EGFR expression in mCRC patients were associated with poorer survival outcomes. Mechanistically, USP21 was found to enhance EGFR stability by deubiquitinating EGFR, leading to reduced EGFR degradation. USP21-KO colon cancer cells exhibited significantly reduced proliferation, migration, colony formation, and 3D tumor spheroid formation in response to EGF. Furthermore, the tumorigenic activity in vivo was markedly diminished in NSG mice xenografted with USP21-KO colon cancer cells. Importantly, BAY-805 demonstrated a notable inhibitory effect on the formation of 3D tumor spheroids in colorectal cancer cells stimulated with EGF. These findings suggest that USP21 could be a valuable therapeutic target and predictive biomarker for managing mCRC driven by EGF. |
| format | Article |
| id | doaj-art-6eaf66d2c4fa4c239a7006f37e5382af |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-6eaf66d2c4fa4c239a7006f37e5382af2025-08-20T02:32:25ZengNature Publishing GroupCell Death Discovery2058-77162024-12-0110111310.1038/s41420-024-02255-1USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancerJi Hye Shin0Mi-Jeong Kim1Ji Young Kim2Bongkum Choi3Yeeun Kang4Seo Hyun Kim5Ha-Jeong Lee6Dohee Kwon7Yong Beom Cho8Kyeong Kyu Kim9Eunyoung Chun10Ki-Young Lee11Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineDepartment of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineDepartment of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineDepartment of Medicine, Sungkyunkwan University School of MedicineDepartment of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineDepartment of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineDepartment of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineBioanalysis Center, GenNBio Inc.Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of MedicineSamsung Medical Center, Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University School of MedicineResearch and Development Center, CHA Vaccine InstituteDepartment of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineAbstract The emerging role of ubiquitin-specific peptidase 21 (USP21) in stabilizing Fra-1 (FOSL1) highlights its involvement in promoting colorectal cancer (CRC) metastasis. Additionally, a reciprocal link between EGFR signaling and Fra-1 activation has been identified, mediated through matrix metalloproteinases (MMPs). However, the functional implications of the USP21-EGFR signaling axis in metastatic CRC (mCRC) are not fully understood. To investigate the clinical correlation between USP21 and EGFR expression, RNA-Seq data from tumor tissues (n = 27) and matched normal tissues (n = 27) of 27 mCRC patients were analyzed. Functional studies were performed, including the use of CRISPR/Cas9 to generate USP21-knockout (USP21-KO) CRC cells, in vitro assays for cancer progression and tumor formation, in vivo xenograft assays in NSG mice. Additionally, the therapeutic effect of the USP21 inhibitor, BAY-805, was evaluated. We found that elevated levels of USP21 and EGFR expression in mCRC patients were associated with poorer survival outcomes. Mechanistically, USP21 was found to enhance EGFR stability by deubiquitinating EGFR, leading to reduced EGFR degradation. USP21-KO colon cancer cells exhibited significantly reduced proliferation, migration, colony formation, and 3D tumor spheroid formation in response to EGF. Furthermore, the tumorigenic activity in vivo was markedly diminished in NSG mice xenografted with USP21-KO colon cancer cells. Importantly, BAY-805 demonstrated a notable inhibitory effect on the formation of 3D tumor spheroids in colorectal cancer cells stimulated with EGF. These findings suggest that USP21 could be a valuable therapeutic target and predictive biomarker for managing mCRC driven by EGF.https://doi.org/10.1038/s41420-024-02255-1 |
| spellingShingle | Ji Hye Shin Mi-Jeong Kim Ji Young Kim Bongkum Choi Yeeun Kang Seo Hyun Kim Ha-Jeong Lee Dohee Kwon Yong Beom Cho Kyeong Kyu Kim Eunyoung Chun Ki-Young Lee USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer Cell Death Discovery |
| title | USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer |
| title_full | USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer |
| title_fullStr | USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer |
| title_full_unstemmed | USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer |
| title_short | USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer |
| title_sort | usp21 egfr signaling axis is functionally implicated in metastatic colorectal cancer |
| url | https://doi.org/10.1038/s41420-024-02255-1 |
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