E2‐EPF UCP, one of member of E2 enzyme family, has been demonstrated to interact with pVHL and catalyze an E3‐independent ubiquitylation of pVHL, followed by the destruction of pVHL via 26S proteasome.[24, 28, 29, 30] WSB1, a newly identified E3 ligase for pVHL, was shown to promote cancer invasion and metastasis through its effect on pVHL.[25] In the present study, we discovered that OTUD6B, a member of OTU DUBs, is able to remove the ubiquitin conjugation of pVHL and stabilize pVHL in HCC cells. This evidence concerns the gene VHL and cancer.