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

Abstract

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.

MicroRNA-155-5p Targets JADE-1, Promoting Proliferation, Migration, and Invasion in Clear Cell Renal Cell Carcinoma Cells

“…To our knowledge, there are no prior reports of Jade-1 with respect to the metastatic phenotypes of proliferation, migration, and invasion in ccRCC, though there are studies highlighting the role of VHL in this regard [53][54][55]. Due to the prominent role of VHL in ccRCC, and its reported strong interaction with Jade-1, this is a potential mechanistic axis for study.…”

Interaction network of human early embryonic transcription factors

“…HEK293 cells were seeded in 10 cm dishes; 24 h later, tetracycline at a final concentration of 2 μg/ml was added to induce the expression of targeted protein. ChIP-seq assays performed as previously described (Ma et al, 2022 ). In brief, HEK293 cells were cross-linked with 1% formaldehyde for 10 min at room temperature.…”

An EBNA1-YAP signaling axis drives immune escape through CD276 in EBV-associated gastric cancer

“…ChIP-sequencing and ChIP-qPCR ChIP-seq assay was performed as described previously (53). In brief, GT38 cells were transfected with FLAG-YAP1 overexpression construct using polyethyleneimine (PEI) DNA transfection reagent and after 48h were cross-linked with 1% formaldehyde for 10min, followed by 5min 125mM glycine treatment to stop the reaction.…”