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WSB1 promotes tumor metastasis by inducing pVHL degradation.

Genes & development (2015-11-08)
Jung Jin Kim, Seung Baek Lee, Jinsung Jang, Sang-Yeop Yi, Sun-Hyun Kim, Sang-Ah Han, Jong-Min Lee, Seo-Yun Tong, Nicole D Vincelette, Bowen Gao, Ping Yin, Debra Evans, Dong Wook Choi, Bo Qin, Tongzheng Liu, Haoxing Zhang, Min Deng, Jin Jen, Jun Zhang, Liewei Wang, Zhenkun Lou
ABSTRACT

The von Hippel-Lindau tumor suppressor pVHL is 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 show that WD repeat 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, WSB1 up-regulates the expression of HIF-1α's target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1 protein 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.

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