WSB1 promotes tumor metastasis by inducing pVHL degradation

ThevonHippel-Lindau tumor suppressorpVHLis an E3 ligase that targets hypoxia-inducible factors (HIFs).Mutation of VHL results in HIF up-regulation and contributes to processes related to tumor progression such as invasion, metastasis, and angiogenesis.However, very little is known with regard to post-transcriptional regulation of pVHL. Here we showthatWDrepeat and SOCS box-containing protein 1 (WSB1) is a negative regulator of pVHL through WSB1’s E3 ligase activity. Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby stabilizing HIF under both normoxic and hypoxic conditions. As a consequence, WSB1up-regulates the expression of HIF-1α’s target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1protein level negatively correlates with pVHL level and metastasis-free survival in clinical samples. This work reveals a new mechanism of pVHL’s regulation by which cancer acquires invasiveness and metastatic tendency.