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

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.

• Authors: Baohui Liu, Huimin Dong, Xi Lin, Xiangsheng Yang, Xiaojing Yue, Jian Yang, Yuntao Li, Liquan Wu, Xiaonan Zhu, Shenqi Zhang, Daofeng Tian, Junmin Wang, Qiang Cai, Shanping Mao, Qianxue Chen, Jiang Chang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 50 Pg. 82411-82423 (Dec 13 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27705942 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• CDH1 protein, human
• Cadherins
• Claudins
• SNAI1 protein, human
• Snail Family Transcription Factors
• RND3 protein, human
• rho GTP-Binding Proteins

Topics

• Animals
• Antigens, CD
• Brain Neoplasms (enzymology, genetics, pathology)
• Cadherins (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Claudins (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Glioblastoma (enzymology, genetics, pathology)
• Humans
• Male
• Mice, Nude
• Neoplasm Invasiveness
• Protein Binding
• Proteolysis
• RNA Interference
• Signal Transduction
• Snail Family Transcription Factors (genetics, metabolism)
• Transfection
• Ubiquitination
• rho GTP-Binding Proteins (genetics, metabolism)