title: Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity.
abstract: Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model. We found that RND3 expression was significantly decreased in human glioblastoma. The levels of RND3 expression were inversely correlated with Notch activity, tumor size, and tumor cell proliferation, and positively correlated with patient survival time. We demonstrated that RND3 functioned as an endogenous repressor of the Notch transcriptional complex. RND3 physically interacted with NICD, CSL, and MAML1, the Notch transcriptional complex factors, promoted NICD ubiquitination, and facilitated the degradation of these cofactor proteins. We further revealed that RND3 facilitated the binding of NICD to FBW7, a ubiquitin ligase, and consequently enhanced NICD protein degradation. Therefore, Notch transcriptional activity was inhibited. Forced expression of RND3 repressed Notch signaling, which led to the inhibition of glioblastoma cell proliferation in vitro and tumor growth in the xenograft mice in vivo. Downregulation of RND3, however, enhanced Notch signaling activity, and subsequently promoted glioma cell proliferation. Inhibition of Notch activity abolished RND3 deficiency-mediated GBM cell proliferation. We conclude that downregulation of RND3 is responsible for the enhancement of Notch activity that promotes glioblastoma genesis.
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Baohui
authors.initials: B
authors.lastname: Liu
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, 77030.
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, Texas, 77030.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neurology, 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, Texas, 77030.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yue
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, 77030.
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: Andrade
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Liquan
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Shenqi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Tian
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
authors.forename: Qizuan
authors.initials: Q
authors.lastname: Chen
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 Neurosurgery, 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, Texas, 77030.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D047368:Tumor Burden; D054875:Ubiquitination; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D051880:Receptors, Notch; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins
keywords: GBM; RND3; notch signaling; ubiquitination