The most common vhl point mutation r167q in hereditary vhl disease interferes with cell plasticity regulation

Abstract

Von Hippel–Lindau disease (VHL) is a rare hereditary syndrome due to mutations of the VHL tumor suppressor gene. Patients harboring the R167Q mutation of the VHL gene have a high risk of developing ccRCCs. We asked whether the R167Q mutation with critical aspects of pseudo-hypoxia interferes with tumor plasticity. For this purpose, we used wild‐type VHL (WT‐VHL) and VHL‐R167Q reconstituted cells. We showed that WT‐VHL and VHL‐R167Q expression had a simi-lar effect on cell morphology and colony formation. However, cells transfected with VHL‐R167Q display an intermediate, HIF2‐dependent, epithelial–mesenchymal phenotype. Using RNA se-quencing, we showed that this mutation upregulates the expression of genes involved in the hy-poxia pathway, indicating that such mutation is conferring an enhanced pseudo‐hypoxic state. Im-portantly, this hypoxic state correlates with the induction of genes belonging to epithelial–mesen-chymal transition (EMT) and stemness pathways, as revealed by GSEA TCGA analysis. Moreover, among these deregulated genes, we identified nine genes specifically associated with a poor patient survival in the TCGA KIRC dataset. Together, these observations support the hypothesis that a dis-crete VHL point mutation interferes with tumor plasticity and may impact cell behavior by exacer-bating phenotypic switching. A better understanding of the role of this mutation might guide the search for more effective treatments to combat ccRCCs.