In ccRCC cells, lack of functional pVHL due to a VHL gene loss of function through the biallelic inactivation prevents from HIF-1α and HIF-2α polyubiquitination and subsequent proteasome-mediated degradation, even under normoxic conditions, allowing them to increasingly accumulate and form stable HIF-1/2 heterodimers, what results in their pathological constitutive activation. This evidence concerns the gene EPAS1 and nonpapillary renal cell carcinoma.