Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma
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.
Authors
- Yi Gao (ORCID: https://orcid.org/0000-0002-3095-7888)
- Bingbing Zha (ORCID: https://orcid.org/0000-0002-4927-8439)
- Mingen Lin (ORCID: https://orcid.org/0000-0002-4665-5120)
- Jiaxi Li (ORCID: https://orcid.org/0000-0002-0873-7109)
- Song Fan (ORCID: https://orcid.org/0000-0002-6387-9361)
- Lei Lv (ORCID: https://orcid.org/0000-0003-4820-3125)
- Xue Sun (ORCID: https://orcid.org/0000-0002-1097-2933)
- Kai Wang (ORCID: https://orcid.org/0000-0002-0137-1247)
- Hui Yang (ORCID: https://orcid.org/0000-0002-2865-5311)
- Ziyi Cui
- Yanping Xu (ORCID: https://orcid.org/0000-0003-2750-5466)
- Yue Dai (ORCID: https://orcid.org/0000-0003-4872-2064)
- Xinyu Zhao (ORCID: https://orcid.org/0000-0002-5128-4424)
- Hongchen Li (ORCID: https://orcid.org/0009-0006-2317-8305)
- Ziyin Tian (ORCID: https://orcid.org/0000-0002-8362-3312)
Institutions
- Tongji University (CN)
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
- Huashan Hospital (CN)
- Tongji Hospital (CN)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1038/s41419-025-07412-7
- Citations
- 9
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 10.36
Funders
- National Natural Science Foundation of China
- Shanghai Rising-Star Program
- Fundamental Research Funds for the Central Universities
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning