WSB1 promotes tumor metastasis by inducing pVHL degradation

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 WangZhenkun Lou

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2244-2257
Number of pages14
JournalGenes and Development
Volume29
Issue number21
DOIs
StatePublished - Nov 1 2015

Keywords

  • Degradation
  • E3 ligase
  • HIFs
  • Metastasis
  • PVHL
  • WSB1

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Kim, J. J., Lee, S. B., Jang, J., Yi, S. Y., Kim, S. H., Han, S. A., Lee, J. M., Tong, S. Y., Vincelette, N. D., Gao, B., Yin, P., Evans, D., Choi, D. W., Qin, B., Liu, T., Zhang, H., Deng, M., Jen, J., Zhang, J., ... Lou, Z. (2015). WSB1 promotes tumor metastasis by inducing pVHL degradation. Genes and Development, 29(21), 2244-2257. https://doi.org/10.1101/gad.268128.115