WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer
Abstract Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor β (ERβ). However, clinical strategies for CRC therapy associated with ERβ are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estr...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05956-0 |
| _version_ | 1797778659839311872 |
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| author | Tianqi Liu Min Zhao Lin Peng Jiangbo Chen Pu Xing Pin Gao Lei Chen Xiaowen Qiao Zaozao Wang Jiabo Di Hong Qu Beihai Jiang Xiangqian Su |
| author_facet | Tianqi Liu Min Zhao Lin Peng Jiangbo Chen Pu Xing Pin Gao Lei Chen Xiaowen Qiao Zaozao Wang Jiabo Di Hong Qu Beihai Jiang Xiangqian Su |
| author_sort | Tianqi Liu |
| collection | DOAJ |
| description | Abstract Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor β (ERβ). However, clinical strategies for CRC therapy associated with ERβ are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estrogen-induced inhibition of metastasis through the ERβ/TGFBR1 signaling axis. WFDC3 interacts with ERβ and increases its protein stability by inhibiting its proteasome-dependent degradation. WFDC3 represses TGFBR1 expression through ERβ-mediated transcription. Blocking TGFβ signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERβ pathway in CRC patients. |
| first_indexed | 2024-03-12T23:20:38Z |
| format | Article |
| id | doaj.art-c223dd527ff9405d86aa0e9e02f7cefd |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T23:20:38Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-c223dd527ff9405d86aa0e9e02f7cefd2023-07-16T11:29:43ZengNature Publishing GroupCell Death and Disease2041-48892023-07-0114711410.1038/s41419-023-05956-0WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancerTianqi Liu0Min Zhao1Lin Peng2Jiangbo Chen3Pu Xing4Pin Gao5Lei Chen6Xiaowen Qiao7Zaozao Wang8Jiabo Di9Hong Qu10Beihai Jiang11Xiangqian Su12Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteSchool of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore DCKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteCenter for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking UniversityKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & InstituteAbstract Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor β (ERβ). However, clinical strategies for CRC therapy associated with ERβ are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estrogen-induced inhibition of metastasis through the ERβ/TGFBR1 signaling axis. WFDC3 interacts with ERβ and increases its protein stability by inhibiting its proteasome-dependent degradation. WFDC3 represses TGFBR1 expression through ERβ-mediated transcription. Blocking TGFβ signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERβ pathway in CRC patients.https://doi.org/10.1038/s41419-023-05956-0 |
| spellingShingle | Tianqi Liu Min Zhao Lin Peng Jiangbo Chen Pu Xing Pin Gao Lei Chen Xiaowen Qiao Zaozao Wang Jiabo Di Hong Qu Beihai Jiang Xiangqian Su WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer Cell Death and Disease |
| title | WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer |
| title_full | WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer |
| title_fullStr | WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer |
| title_full_unstemmed | WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer |
| title_short | WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer |
| title_sort | wfdc3 inhibits tumor metastasis by promoting the erβ mediated transcriptional repression of tgfbr1 in colorectal cancer |
| url | https://doi.org/10.1038/s41419-023-05956-0 |
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