Ectopic OTUD6B inhibited ubiquitylation and prolonged the half-life of majority of pVHL mutants, while OTUD6B knockdown blunted the effects of pVHL mutants in ccRCC cells, including cell migration inhibition and HIF-2α stabilization, indicating OTUD6B stabilized tumor-derived pVHL missense mutants and promoted their activity in ccRCC cells. This evidence concerns the gene OTUD6B and nonpapillary renal cell carcinoma.