RND3 promotes Snail 1 protein degradation and inhibits glioblastoma cell migration and invasion.

Baohui Liu,Xi Lin,Shanping Mao,Junmin Wang,Xiangsheng Yang,Xiaonan Zhu,Huimin Dong,Daofeng Tian,Qiang Cai,Shenqi Zhang,Jian Yang,Yuntao Li,Liquan Wu,Qianxue Chen,Xiaojing Yue,Jiang Chang

doi:10.18632/oncotarget.12396

Baohui Liu, Xi Lin + Show 14 more

Open Access

https://doi.org/10.18632/oncotarget.12396

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Abstract

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.

Highlights

Glioblastoma multiforme (GBM, World Health Organization grade IV) is one of the most common primary tumors of the central nervous system
By screening human glioblastoma multiforme (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
Significant downregulation of E-cadherin, claudin and RND3 protein levels were detected in human GBM tissues

Summary

Introduction

Glioblastoma multiforme (GBM, World Health Organization grade IV) is one of the most common primary tumors of the central nervous system. GBM are the highest grade of gliomas, given the characteristic abilities of high invasion, migration, and proliferation. Surgery followed by radiation and chemotherapy is the standard therapy for glioblastoma patients. Despite standard and targeted therapies, the median overall survival of GBM patients remains just over 1 year [1]. Glioblastoma migration and invasion occurs at multiple stages of cancer progression and is a clinical obstacle for therapy. Suppression of glioblastoma cell migration and invasion will provide an effective therapeutic strategy

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