title: 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.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Baohui
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Dong
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yue
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Liquan
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Shenqi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Tian
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
authors.forename: Shanping
authors.initials: S
authors.lastname: Mao
authors.affiliation: Department of Neurological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Qianxue
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D057167:Claudins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins
keywords: RND3; multiform glioblastoma; snail1 signaling