VHL and nonpapillary renal cell carcinoma: VHL is an important tumor suppressor gene, and although VHL inactivation is common in various tumor types, ccRCC exhibits significant heterogeneity in VHL mutations.[2,59] The VHL protein complex facilitates the recruitment of the E3 ligase complex, leading to ubiquitination and subsequent degradation of hypoxia-inducible factor α (HIFα).