2. Academic Validation
  3. KGF impedes TRIM21-enhanced stabilization of keratin 10 mediating differentiation in hypopharyngeal cancer

KGF impedes TRIM21-enhanced stabilization of keratin 10 mediating differentiation in hypopharyngeal cancer

  • Cell Signal. 2025 Mar:127:111614. doi: 10.1016/j.cellsig.2025.111614.
Fangyu Chai 1,  Guangyi Wang 1,  Yibang Shen 1,  Yanfang Niu 2,  Yichuan Huang 1,  Tao Fu 1,  Tao Yang 3,  Yan Jiang 4,  Jisheng Zhang 5
Affiliations

Affiliations

  • 1 Key Laboratory, Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, 266003 Qingdao, China.
  • 2 Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
  • 3 Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Higher Education Key Laboratory of Tumor Immunology & Targeted Drug Development in Shanxi Province, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key laboratory of Digestive Disease & Organ Transplantation in Shanxi Province, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China. Electronic address: yangtao056cn@sxmu.edu.cn.
  • 4 Key Laboratory, Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, 266003 Qingdao, China. Electronic address: jiangyanoto@qdu.edu.cn.
  • 5 Key Laboratory, Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, 266003 Qingdao, China. Electronic address: zhangjs@qdu.edu.cn.
PMID: 39848455 DOI: 10.1016/j.cellsig.2025.111614
Abstract

KGF, also known as FGF7, is a member of the Fibroblast Growth Factor (FGF) family that binds with high affinity to the FGF receptor 2b (FGFR2b) and regulates various cellular processes, including cell proliferation and differentiation in a variety of tumors. However, its potential role in hypopharyngeal Cancer (HPC) remains largely unknown. In our study, we observed increased expression of FGFR2b in HPC. KGF treatment inhibited the expression of the differentiation marker keratin 10 (K10) protein at the post-transcriptional level in FaDu cells. Furthermore, treatment with the Proteasome Inhibitor MG132 was found to attenuate KGF-induced K10 reduction, suggesting the involvement of the ubiquitin-proteasome system. Using mass spectrometry and immunoprecipitation analysis, we identified the E3 ubiquitin Ligase TRIM21 as a K10-interacting protein. Unexpectedly, instead of causing degradation, TRIM21 enhanced K10 protein stability through K6-linked ubiquitination of K10 at lysine 163 (K163) in the context of KGF exposure. Meanwhile, KGF treatment decreased TRIM21 protein levels, which were regulated by the p38 MAPK pathway, leading to K48-linked ubiquitination-mediated degradation of TRIM21. Notably, TRIM21 knockdown significantly promoted proliferation, inhibited differentiation and migration of FaDu cells, whereas TRIM21 overexpression had opposite effects in vitro and suppressed xenograft tumor growth in vivo. Our study demonstrates that TRIM21 may act as a tumor suppressor in HPC. However, TRIM21 overexpression decreased the sensitivity of FaDu cells to 5-fluorouracil, whereas TRIM21 knockdown or KGF administration significantly increased 5-fluorouracil sensitivity. Taken together, these findings highlight the intricate balance between protein stabilization and degradation orchestrated by KGF. This ubiquitination-mediated non-degradation mechanism of TRIM21 may provide novel therapeutic strategies for HPC and Other cancers.

Keywords

FGF7; FGFR2b; K6-linked ubiquitination; KGF; Keratin 10; TRIM21.

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