Details

Autor(en) / Beteiligte

• Ma, Xueyou
• Tan, Zenglai
• Zhang, Qin
• Ma, Kaifang
• Xiao, Jun
• Wang, Xiong
• Wang, Yanan
• Zhong, Mengjie
• Wang, Yu
• Li, Jing
• Zeng, Xing
• Guan, Wei
• Wang, Shaogang
• Gong, Kan
• Wei, Gong-Hong
• Wang, Zhihua

Titel

VHL Ser65 mutations enhance HIF2[alpha] signaling and promote epithelial-mesenchymal transition of renal cancer cells

Ist Teil von

• Cell & bioscience, 2022-05, Vol.12 (1)

Ort / Verlag

BioMed Central Ltd

Erscheinungsjahr

2022

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. 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 [beta]-domain and nearby the interaction sites with hypoxia-inducing factor [alpha] (HIF[alpha]), is highly conserved among different species. We observed gain of functions in VHL mutations, thereby stabilizing HIF2[alpha] protein and reprograming HIF2[alpha] genome-wide target gene transcriptional programs. Further analysis of independent cohorts of patients with renal carcinoma revealed specific HIF2[alpha] 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. 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.