Overexpression of SHARPIN leads to elevated intracellular HIF2α in patients with Renal cell carcinoma. SHARPIN can promote polyubiquitination of pVHL and thus degradation by the proteasome, which causes HIF-2α to escape the fate of ubiquitination and successfully into the nucleus to function. Here, EPAS1 is linked to hereditary clear cell renal cell carcinoma.