University of Oulu

Ma, X., Tan, Z., Zhang, Q. et al. VHL Ser65 mutations enhance HIF2α signaling and promote epithelial-mesenchymal transition of renal cancer cells. Cell Biosci 12, 52 (2022).

VHL Ser65 mutations enhance HIF2α signaling and promote epithelial-mesenchymal transition of renal cancer cells

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Author: Ma, Xueyou1,2; Tan, Zenglai3; Zhang, Qin3;
Organizations: 1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
2Department of Urology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
3Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014, Oulu, Finland
4Department of Urology, Peking University First Hospital, Beijing, 100034, China
5Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
6Ministry of Education Key Laboratory of Metabolism and Molecular Medicine & Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, 200032, China
7Department of Bioinformatics, Center for Translational Medicine, Naval Military Medical University, Shanghai, 200433, China
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 11.4 MB)
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Language: English
Published: Springer Nature, 2022
Publish Date: 2022-09-29


Background: Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic neoplastic disorder caused by germline mutation or deletion of the VHL gene, characterized by the tendency to develop multisystem benign or malignant tumors. The mechanism of VHL mutants in pathogenicity is poorly understand.

Results: Here we identified heterozygous missense mutations c.193T > C and c.194C > G in VHL in several patients from two Chinese families. These mutations are predicted to cause Serine (c.193T > C) to Proline and Tryptophan (c.194C > G) substitution at residue 65 of VHL protein (p.Ser65Pro and Ser65Trp). Ser65 residue, located within the β-domain and nearby the interaction sites with hypoxia-inducing factor α (HIFα), is highly conserved among different species. We observed gain of functions in VHL mutations, thereby stabilizing HIF2α protein and reprograming HIF2α genome-wide target gene transcriptional programs. Further analysis of independent cohorts of patients with renal carcinoma revealed specific HIF2α gene expression signatures in the context of VHL Ser65Pro or Ser65Trp mutation, showing high correlations with hypoxia and epithelial-mesenchymal transition signaling activities and strong associations with poor prognosis.

Conclusions: Together, our findings highlight the crucial role of pVHL-HIF dysregulation in VHL disease and strengthen the clinical relevance and significance of the missense mutations of Ser65 residue in pVHL in the familial VHL disease.

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Series: Cell & bioscience
ISSN: 2045-3701
ISSN-E: 2045-3701
ISSN-L: 2045-3701
Volume: 12
Issue: 1
Article number: 52
DOI: 10.1186/s13578-022-00790-x
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This study is supported by National Natural Science Foundation of China (No. 81974400, 82173068, 82073082, 81872081, 82172617), Tongji Hospital Pilot Project Fund (No. 2019CR101), the Fudan University Recruit Fund, the Jane and Aatos Erkko Foundation and the Sigrid Juseliuksen Saatio.
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