RND3 promotes Snail 1 protein degradation and inhibits glioblastoma cell migration and invasion
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Baohui Liu1,*, Huimin Dong1,*, Xi Lin2, Xiangsheng Yang2, Xiaojing Yue2, Jian Yang1, Yuntao Li1, Liquan Wu1, Xiaonan Zhu1, Shenqi Zhang1, Daofeng Tian1, Junmin Wang1, Qiang Cai1, Shanping Mao3, Qianxue Chen1, Jiang Chang2
1Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
2Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA
3Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
*These authors contributed equally to this work
Jiang Chang, email: [email protected]
Qianxue Chen, email: [email protected]
Keywords: RND3, multiform glioblastoma, snail1 signaling
Received: May 20, 2016 Accepted: September 24, 2016 Published: October 01, 2016
Activation of Snail1 signaling promotes the migration and invasion of multiple tumors, including glioblastoma multiforme (GBM). However, the molecular mechanism that augments Snail1 signaling during GBM cell migration and invasion remains largely unknown. Identification of the factors that regulate Snail1 signaling is critical to block tumor cell migration and invasion. By screening human GBM specimens, we found that the expression levels of small GTPase RND3 positively correlated with the expression levels of E-cadherin and claudin, the glioblastoma migration biomarkers negatively regulated by Snail1. Downregulation of E-cadherin and claudin has been associated with the migration and invasion of GBM cells. We demonstrated that RND3 functioned as an endogenous inhibitor of the Snail-directed transcriptional regulation. RND3 physically interacted with Snail1 protein, enhanced Snail1 ubiquitination, and facilitated the protein degradation. Forced expression of RND3 inhibited Snail1 activity, which in turn blocked glioblastoma cell migration and invasion in vitro in cell culture and in vivo in GBM xenograft mice. In contrast, downregulation of RND3 augmented Snail1 activity, and subsequently decreased E-cadherin expression, eventually promoted glioblastoma cell migration and invasion. The pro-migration induced by RND3 downregulation was attenuated by Snail1 knockdown. The findings partially explain why Snail1 activity is augmented in GBM, and defines a new function of RND3 in GBM cell migration and invasion.
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