title: Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells.
abstract: 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.
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Cao
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Dong
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Guanyu
authors.initials: G
authors.lastname: Lin
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Zhejiang Province Key Laboratory of Medical Molecular Imaging, The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute for Individualized Medicine, Hangzhou First People's Hospital, Hangzhou, China.
authors.forename: Nengming
authors.initials: N
authors.lastname: Lin
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand.
authors.forename: Yongchuan
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ding
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Meidan
authors.initials: M
authors.lastname: Ying
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. yang924@zju.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005260:Female; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness / Q000473:pathology; D012516:Osteosarcoma / Q000473:pathology*; D011506:Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014161:Transduction, Genetic
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D034741:RNA, Small Interfering; C120287:WSB1 protein, human