Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells.

Intratumoral hypoxia occurs in many solid tumors, where it is associated with the development of metastatic character. However, the connections between these phenomena are not fully understood. In this study, we define an integrative role for the E3 ubiquitin ligase subunit WSB1. In primary osteosarcomas, increased levels of WSB1 correlated with pulmonary metastatic potential. RNAi-mediated attenuation of WSB1 or disruption of its E3 ligase activity potently suppressed tumor metastasis. Quantitative proteomic and functional analyses revealed that WSB1 ubiquitylates the Rho-binding protein RhoGDI2 and promotes its proteasomal degradation, thereby activating Rac1 to stimulate tumor cell motility and invasion. Our findings show how WSB1 regulates key steps of the metastatic cascade in hypoxia-driven osteosarcoma, and they highlight a candidate therapeutic target to potentially improve the survival of patients with metastatic disease.

• Publication year

  2015

• Venue

  Cancer Research

• Publication date

  2015-09-30

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1158/0008-5472.CAN-15-0711PMID 26424695
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Osteosarcoma.

  2016cited by this paper
• Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology.

  2014cited by this paper
• The Oxidation States of DJ-1 Dictate the Cell Fate in Response to Oxidative Stress Triggered by 4-HPR: Autophagy or Apoptosis?

  2014cited by this paper
• E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα

  2014cited by this paper
• Potential role of WSB1 isoforms in growth and survival of neuroblastoma cells

  2014cited by this paper
• Hypoxia Promotes Migration and Induces CXCR4 Expression via HIF-1α Activation in Human Osteosarcoma

  2014cited by this paper
• HIF1 regulates WSB‐1 expression to promote hypoxia‐induced chemoresistance in hepatocellular carcinoma cells

  2013cited by this paper
• Guiding cell migration by tugging.

  2013cited by this paper
• Rictor encounters RhoGDI2

  2013cited by this paper
• Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells

  2013cited by this paper
• Risk factors for metastatic disease at presentation with osteosarcoma: an analysis of the SEER database.

  2013cited by this paper
• Heading off with the herd: how cancer cells might maneuver supernumerary centrosomes for directional migration

  2012cited by this paper
• Rictor regulates cell migration by suppressing RhoGDI2

  2012cited by this paper
• Expression and stability of hypoxia inducible factor 1α in osteosarcoma

  2012cited by this paper
• Predicting chemosensitivity in osteosarcoma prior to chemotherapy: An investigational study of biomarkers with immunohistochemistry.

  2012cited by this paper
• mechanisms of disease Oxygen Sensing , Homeostasis , and Disease

  2011cited by this paper
• RhoGDI2 antagonizes ovarian carcinoma growth, invasion and metastasis

  2011cited by this paper
• Targeting hypoxia in cancer therapy

  2011cited by this paper
• Oxygen sensing, homeostasis, and disease.

  2011cited by this paper
• Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing’s sarcoma

  2011cited by this paper
• HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression

  2011cited by this paper
• Hypoxia-inducible factors and the response to hypoxic stress.

  2010cited by this paper
• RhoGDI: A rheostat for the Rho switch.

  2010cited by this paper
• Prognostic markers in osteosarcoma

  2010cited by this paper
• Heparanase participates in the growth and invasion of human U-2OS osteosarcoma cells and its close relationship with hypoxia-inducible factor-1α in osteosarcoma.

  2010cited by this paper
• Osteosarcoma.

  2009cited by this paper
• Pathways of metastasis suppression in bladder cancer

  2009cited by this paper
• Silencing of D4-GDI Inhibits Growth and Invasive Behavior in MDA-MB-231 Cells by Activation of Rac-dependent p38 and JNK Signaling

  2009cited by this paper
• Ubiquitination and Degradation of Homeodomain-interacting Protein Kinase 2 by WD40 Repeat/SOCS Box Protein WSB-1*

  2008cited by this paper
• The WSB1 Gene Is Involved in Pancreatic Cancer Progression

  2008cited by this paper
• Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease.

  2008cited by this paper
• RhoGDI2: a new metastasis suppressor gene: discovery and clinical translation.

  2007cited by this paper
• Overexpression of hypoxia-inducible factor-1alpha in human osteosarcoma: correlation with clinicopathological parameters and survival outcome.

  2007cited by this paper
• Increased WSB1 copy number correlates with its over‐expression which associates with increased survival in neuroblastoma

  2006cited by this paper
• Primary bone osteosarcoma in the pediatric age: state of the art.

  2006cited by this paper
• Rho GTPases: biochemistry and biology.

  2005cited by this paper
• The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate

  2005cited by this paper
• RhoGDI: multiple functions in the regulation of Rho family GTPase activities.

  2005cited by this paper
• Reduced Expression of Metastasis Suppressor RhoGDI2 Is Associated with Decreased Survival for Patients with Bladder Cancer

  2004cited by this paper
• Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

  2003cited by this paper
• The SOCS box: a tale of destruction and degradation.

  2002cited by this paper
• RhoGDI2 is an invasion and metastasis suppressor gene in human cancer.

  2002cited by this paper
• Structure-activity relationships in flexible protein domains: regulation of rho GTPases by RhoGDI and D4 GDI.

  2001cited by this paper
• The Rac–RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI

  2000cited by this paper

• Single-cell analysis links DCUN1D5 to immune remodeling and cisplatin resistance in recurrent osteosarcoma

  2025cites this paper
• Okanin Suppresses the Growth of Colorectal Cancer Cells by Targeting at Peroxiredoxin 5

  2025cites this paper
• Emerging research themes in drug resistance in osteosarcoma: a 25-year bibliometric and visualized analysis

  2025cites this paper
• WSB-1 regulates DNA repair and the response to DNA damage response inhibitors in breast cancer

  2025cites this paper
• A novel perspective on bone tumors: advances in organoid research

  2025cites this paper
• Comparative proteomic analysis of retinal hypoxia-ischemia in an acute ocular hypertension model using tandem mass tag-based quantitative proteomics.

  2024cites this paper
• WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination

  2024cites this paper
• WSB1, a Hypoxia-Inducible E3 Ligase, Promotes Myofibroblast Accumulation and Attenuates Alveolar Epithelial Regeneration in Mouse Lung Fibrosis.

  2024cites this paper
• Recently reported cell migration inhibitors: Opportunities and challenges for antimetastatic agents.

  2024cites this paper
• The Research Progress of WD Protein Subfamily in Tumor Mechanism

  2024cites this paper
• WSB1 Involvement in Prostate Cancer Progression

  2023influential citation
• Cracking the code: Deciphering the role of the tumor microenvironment in osteosarcoma metastasis.

  2023cites this paper
• AlphaFold2 and its applications in the fields of biology and medicine

  2023cites this paper
• The Dual Function of RhoGDI2 in Immunity and Cancer

  2023cites this paper
• circWSB1 promotes tumor progression in ccRCC via circWSB1/miR-182-5p/WSB1 axis.

  2023cites this paper
• Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer

  2022cites this paper
• Development and Verification of a Hypoxic Gene Signature for Predicting Prognosis, Immune Microenvironment, and Chemosensitivity for Osteosarcoma

  2022cites this paper
• Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10

  2022cites this paper
• The intricate interplay between HIFs, ROS, and the ubiquitin system in the tumor hypoxic microenvironment.

  2022cites this paper
• The Role of Membrane-Associated E3 Ubiquitin Ligases in Cancer

  2022cites this paper
• Targeted therapy of atherosclerosis by zeolitic imidazolate framework-8 nanoparticles loaded with losartan potassium via simultaneous lipid-scavenging and anti-inflammation.

  2022cites this paper
• Identification of Potential WSB1 Inhibitors by AlphaFold Modeling, Virtual Screening, and Molecular Dynamics Simulation Studies

  2022cites this paper
• CUL5–ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to Regulate Cell Proliferation and Autophagy

  2021cites this paper
• Osteosarcoma and Metastasis

  2021cites this paper
• Identifying common transcriptome signatures of cancer by interpreting deep learning models

  2021cites this paper
• WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit

  2021cites this paper
• Immune-related gene expression signatures in colorectal cancer

  2021cites this paper
• Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis.

  2021cites this paper
• Development and Validation of a Hypoxia-Associated Prognostic Signature Related to Osteosarcoma Metastasis and Immune Infiltration

  2021cites this paper
• Development and analysis of long non-coding RNA-associated competing endogenous RNA network for osteosarcoma metastasis

  2021cites this paper
• Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression

  2021cites this paper
• Identification of candidate targets for the diagnosis and treatment of atherosclerosis by bioinformatics analysis.

  2021cites this paper
• High expression of WSB1 is associated with poor prognosis in hepatocellular carcinoma and affects epithelial-mesenchymal transition.

  2020cites this paper
• Cullin RING Ligase 5 (CRL-5): Neddylation Activation and Biological Functions.

  2020cites this paper
• Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

  2020cites this paper
• USP10 Promotes Proliferation of Hepatocellular Carcinoma by Deubiquitinating and Stabilizing YAP/TAZ

  2020cites this paper
• Cullin-RING Ligase 5: Functional characterization and its role in human cancers.

  2020cites this paper
• Sea cucumber Cucumaria frondosa fucoidan inhibits osteosarcoma adhesion and migration by regulating cytoskeleton remodeling

  2020cites this paper
• Correction: Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

  2020cites this paper
• Peripheral blood transcriptome identifies high-risk benign and malignant breast lesions

  2020influential citation
• Identification of Osteosarcoma Metastasis-Associated Gene Biomarkers and Potentially Targeted Drugs Based on Bioinformatic and Experimental Analysis

  2020cites this paper
• WSB1 Regulates c-Myc Expression Through β-catenin Signaling and Forms a Feedforward Circuit Promoting the Development of Cancer

  2020cites this paper
• WSB2 as a target of Hedgehog signaling promoted the malignant biological behavior of Xuanwei lung cancer through regulating Wnt/β-catenin signaling

  2020cites this paper
• Identification of Osteosarcoma Metastasis-Associated Gene Biomarkers and Potentially Targeted Drugs Based on Bioinformatic and Experimental Analysis

  2020cites this paper
• Metastasis risk prediction model in osteosarcoma using metabolic imaging phenotypes: A multivariable radiomics model

  2019cites this paper
• Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma

  2019cites this paper
• The Role of Ubiquitination in Regulating Embryonic Stem Cell Maintenance and Cancer Development

  2019cites this paper
• Hypoxia promotes osteosarcoma cell proliferation and migration through enhancing platelet-derived growth factor-BB/platelet-derived growth factor receptor-β axis.

  2019cites this paper
• Hydroxysafflor yellow A sensitizes ovarian cancer cells to chemotherapeutic agent by decreasing WSB1 expression

  2019cites this paper
• Proteomics in Drug Development: The Dawn of a New Era?

  2019cites this paper
• Investigating age-induced differentially expressed genes and potential molecular mechanisms in osteosarcoma based on integrated bioinformatics analysis

  2019cites this paper
• KLF4 functions as an oncogene in promoting cancer stem cell-like characteristics in osteosarcoma cells

  2018cites this paper
• Classifying Osteosarcoma Using Meta-Analysis of Gene Expression

  2018cites this paper
• Lipopolysaccharide promoted the growth rate of MG-63 cells via the extracellular regulated kinase pathway

  2018cites this paper
• WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer

  2018influential citation
• From genomics to metabolomics: emerging metastatic biomarkers in osteosarcoma

  2018cites this paper
• Proteomic profiling of human decidual immune proteins during Toxoplasma gondii infection.

  2018cites this paper
• Bortezomib sensitizes human osteosarcoma cells to adriamycin‐induced apoptosis through ROS‐dependent activation of p‐eIF2α/ATF4/CHOP axis

  2017cites this paper
• For robust big data analyses: a collection of 150 important pro-metastatic genes

  2017cites this paper
• PLOD2 regulated by transcription factor FOXA1 promotes metastasis in NSCLC

  2017cites this paper
• Biallelic Dicer1 Loss Mediated by aP2-Cre Drives Angiosarcoma.

  2017cites this paper
• Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells

  2017cites this paper
• miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

  2016cites this paper
• The role of cullin 5-containing ubiquitin ligases

  2016cites this paper
• WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation

  2016cites this paper
• The progress about HIFs and bone tumor

  2016cites this paper
• WSB1: from homeostasis to hypoxia

  2016influential citation
• Long noncoding RNA ANRIL is activated by hypoxia-inducible factor-1α and promotes osteosarcoma cell invasion and suppresses cell apoptosis upon hypoxia

  2016cites this paper
• SIRT1 promotes metastasis of human osteosarcoma cells

  2016cites this paper
• Intraepithelial ischemia is a principal factor promoting cancerization of the covering epithelial tissues.

  2016cites this paper