E2‐EPF ubiquitin carrier protein (UCP), one of member of E2 enzyme family, forms a complex with pVHL and catalyzes an E3‐independent ubiquitylation and subsequent destruction of pVHL.[24, 28, 29, 30] Additionally, Trp Asp repeat and suppressors of cytokine signaling box‐containing protein 1 (WSB1), a newly identified E3 ligase for pVHL, has been demonstrated to promote cancer invasion and metastasis through targeting pVHL.[25] Nevertheless, the DUB responsible for removing the ubiquitin linkage of pVHL has not been identified. Here, UBE2S is linked to cancer.