Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma
Abstract Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cancer, and its treatment options remain limited. Therefore, there is an urgent need to discover therapeutic agents for ccRCC treatment. Here, we demonstrate that dimethyl fumarate (DMF), an approved medication for...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-02-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07412-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861575873724416 |
|---|---|
| author | Yue Dai Hongchen Li Shiyin Fan Kai Wang Ziyi Cui Xinyu Zhao Xue Sun Mingen Lin Jiaxi Li Yi Gao Ziyin Tian Hui Yang Bingbing Zha Lei Lv Yanping Xu |
| author_facet | Yue Dai Hongchen Li Shiyin Fan Kai Wang Ziyi Cui Xinyu Zhao Xue Sun Mingen Lin Jiaxi Li Yi Gao Ziyin Tian Hui Yang Bingbing Zha Lei Lv Yanping Xu |
| author_sort | Yue Dai |
| collection | DOAJ |
| description | Abstract Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cancer, and its treatment options remain limited. Therefore, there is an urgent need to discover therapeutic agents for ccRCC treatment. Here, we demonstrate that dimethyl fumarate (DMF), an approved medication for multiple sclerosis [1] and psoriasis, can inhibit the proliferation of ccRCC cells. Mechanistically, hepatocyte nuclear factor 1β (HNF1B), a transcription factor highly expressed in ccRCC, is succinated by DMF at cysteine residues, leading to its proteasomal degradation. Furthermore, HNF1B interacts with and stabilizes Yes-associated protein (YAP), thus DMF-mediated HNF1B degradation decreases YAP protein level and the expression of its target genes, resulting in the suppression of ccRCC cell proliferation. Importantly, oral administration of DMF sensitizes ccRCC to sunitinib treatment and enhances its efficacy in mice. In summary, we provide evidences supporting DMF as a potential drug for clinical treatment of ccRCC by targeting HNF1B and reveal a previously unrecognized role of HNF1B in regulating YAP in ccRCC. |
| format | Article |
| id | doaj-art-8ecff3f34b8c45eabcfcc0767e2a786d |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-8ecff3f34b8c45eabcfcc0767e2a786d2025-02-09T12:56:47ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111210.1038/s41419-025-07412-7Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinomaYue Dai0Hongchen Li1Shiyin Fan2Kai Wang3Ziyi Cui4Xinyu Zhao5Xue Sun6Mingen Lin7Jiaxi Li8Yi Gao9Ziyin Tian10Hui Yang11Bingbing Zha12Lei Lv13Yanping Xu14Fifth People’s Hospital of Shanghai, MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityTongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityFifth People’s Hospital of Shanghai, MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityDepartment of Endocrinology, Fifth People’s Hospital of Shanghai, Fudan UniversityTongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityTongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityFifth People’s Hospital of Shanghai, MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityFifth People’s Hospital of Shanghai, MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityFifth People’s Hospital of Shanghai, MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityFifth People’s Hospital of Shanghai, MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityFifth People’s Hospital of Shanghai, MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityDepartment of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan UniversityDepartment of Endocrinology, Fifth People’s Hospital of Shanghai, Fudan UniversityFifth People’s Hospital of Shanghai, MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityTongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityAbstract Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cancer, and its treatment options remain limited. Therefore, there is an urgent need to discover therapeutic agents for ccRCC treatment. Here, we demonstrate that dimethyl fumarate (DMF), an approved medication for multiple sclerosis [1] and psoriasis, can inhibit the proliferation of ccRCC cells. Mechanistically, hepatocyte nuclear factor 1β (HNF1B), a transcription factor highly expressed in ccRCC, is succinated by DMF at cysteine residues, leading to its proteasomal degradation. Furthermore, HNF1B interacts with and stabilizes Yes-associated protein (YAP), thus DMF-mediated HNF1B degradation decreases YAP protein level and the expression of its target genes, resulting in the suppression of ccRCC cell proliferation. Importantly, oral administration of DMF sensitizes ccRCC to sunitinib treatment and enhances its efficacy in mice. In summary, we provide evidences supporting DMF as a potential drug for clinical treatment of ccRCC by targeting HNF1B and reveal a previously unrecognized role of HNF1B in regulating YAP in ccRCC.https://doi.org/10.1038/s41419-025-07412-7 |
| spellingShingle | Yue Dai Hongchen Li Shiyin Fan Kai Wang Ziyi Cui Xinyu Zhao Xue Sun Mingen Lin Jiaxi Li Yi Gao Ziyin Tian Hui Yang Bingbing Zha Lei Lv Yanping Xu Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma Cell Death and Disease |
| title | Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma |
| title_full | Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma |
| title_fullStr | Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma |
| title_full_unstemmed | Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma |
| title_short | Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma |
| title_sort | dimethyl fumarate promotes the degradation of hnf1b and suppresses the progression of clear cell renal cell carcinoma |
| url | https://doi.org/10.1038/s41419-025-07412-7 |
| work_keys_str_mv | AT yuedai dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT hongchenli dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT shiyinfan dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT kaiwang dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT ziyicui dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT xinyuzhao dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT xuesun dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT mingenlin dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT jiaxili dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT yigao dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT ziyintian dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT huiyang dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT bingbingzha dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT leilv dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma AT yanpingxu dimethylfumaratepromotesthedegradationofhnf1bandsuppressestheprogressionofclearcellrenalcellcarcinoma |