WSB1 promotes tumor metastasis by inducing pVHL degradation
Open accessAbstract
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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VHL activity in tumors can be regulated by WSB1, an E3 ligase that targets pVHL for ubiquitination and proteasomal degradation.
“VHL activity in tumors can be regulated by WSB1, an E3 ligase that targets pVHL for ubiquitination and proteasomal degradation”
From Hypoxic control of metastasis (2016) · cites this paper as [27]
WSB1 expression in tumor cells leads to HIF stabilization under normoxic and hypoxic conditions and correlates with metastasis in cancer patients.
“WSB1 expression in tumor cells leads to HIF stabilization under normoxic and hypoxic conditions and correlates with metastasis in cancer patients”
From Hypoxic control of metastasis (2016) · cites this paper as [27]
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- Authors
- 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., Wang, L., & Lou, Z.
- Affiliations
- Mayo Clinic (US)
- Catholic Kwandong University International St. Mary's Hospital (KR)
- Kyung Hee University (KR)
- Sungkyunkwan University (KR)
- Corresponding author
- Lou, Zhenkun
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-11-01
- Volume
- 29
- Issue
- 21
- Pages
- 2244-2257
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC4647558
- OpenAlex
- W2145983041
- Cited by
- 83
- References
- 64
- Citations by year
- 2026: 3 · 2025: 16 · 2024: 15 · 2023: 8 · 2022: 11 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 6
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA130996, CA148940, CA189666)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Keywords
- WSB1, von Hippel-Lindau protein, E3 ubiquitin ligase, HIF-1α stabilization, hypoxia-inducible factor, metastasis, tumor invasion, proteasomal degradation, post-translational regulation, metastasis-free survival
- MeSH terms
- Cell Movement, HeLa Cells, Humans, Mutation, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Proteins, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Protein Structure, Tertiary, HT29 Cells, Cell Line, Tumor, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination, Protein Stability, HEK293 Cells
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