2. Academic Validation
  3. Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma

Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma

  • Cell Death Dis. 2025 Feb 6;16(1):71. doi: 10.1038/s41419-025-07412-7.
Yue Dai # 1,  Hongchen Li # 2,  Shiyin Fan 1,  Kai Wang 3,  Ziyi Cui 2,  Xinyu Zhao 2,  Xue Sun 1,  Mingen Lin 1,  Jiaxi Li 1,  Yi Gao 1,  Ziyin Tian 1,  Hui Yang 4,  Bingbing Zha 5,  Lei Lv 6,  Yanping Xu 7
Affiliations

Affiliations

  • 1 Fifth 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 University, Shanghai, China.
  • 2 Tongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 3 Department of Endocrinology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
  • 4 Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. hui_yang@fudan.edu.cn.
  • 5 Department of Endocrinology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China. bingbingzha@fudan.edu.cn.
  • 6 Fifth 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 University, Shanghai, China. lvlei@fudan.edu.cn.
  • 7 Tongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. yanpingxu@tongji.edu.cn.
  • # Contributed equally.
PMID: 39915461 DOI: 10.1038/s41419-025-07412-7
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.

Figures
Products