Notably, the mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCCs), while HIFs could be ubiquitinylated by this tumor suppressor protein (VHL), leading to the accumulation of HIF-1α and HIF-2α and regulating the development and inflammation of ccRCC [51]. This evidence concerns the gene EPAS1 and clear cell renal carcinoma.