title: WSB1 promotes tumor metastasis by inducing pVHL degradation.
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.
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Seung Baek
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Jinsung
authors.initials: J
authors.lastname: Jang
authors.affiliation: Department of Pathology, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon 404-834, Republic of Korea;
authors.forename: Sang-Yeop
authors.initials: SY
authors.lastname: Yi
authors.affiliation: Department of Family Medicine, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon 404-834, Republic of Korea;
authors.forename: Sun-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Surgery, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Sang-Ah
authors.initials: SA
authors.lastname: Han
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Seo-Yun
authors.initials: SY
authors.lastname: Tong
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Vincelette
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Bowen
authors.initials: B
authors.lastname: Gao
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA; Mayo Graduate School, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Debra
authors.initials: D
authors.lastname: Evans
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Republic of Korea;
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Choi
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Haoxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Jin
authors.initials: J
authors.lastname: Jen
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA;
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C120287:WSB1 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D046988:Proteasome Endopeptidase Complex; C497446:VHL protein, human
keywords: E3 ligase; HIFs; WSB1; degradation; metastasis; pVHL