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 osteosar...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2015-11, Vol.75 (22), p.4839-4851
Main Authors: Cao, Ji, Wang, Yijie, Dong, Rong, Lin, Guanyu, Zhang, Ning, Wang, Jing, Lin, Nengming, Gu, Yongchuan, Ding, Ling, Ying, Meidan, He, Qiaojun, Yang, Bo
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Bone Neoplasms - pathology
Cell Hypoxia - physiology
Cell Line, Tumor
Chromatin Immunoprecipitation
Female
Fluorescent Antibody Technique
Heterografts
Humans
Mice
Mice, Inbred BALB C
Microscopy, Confocal
Neoplasm Invasiveness - pathology
Osteosarcoma - pathology
Proteins - metabolism
Real-Time Polymerase Chain Reaction
RNA, Small Interfering
Transduction, Genetic
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-15-0711