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.

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

“…Genetic deletion of RND3 promoted mouse ependymal epithelia proliferation, which in turn led to aqueduct stenosis and hydrocephalus development [20]. We also demonstrated an inhibitory role of RND3 in GBM tumorigenesis through targeting Notch signaling [8]. Similar observations were detected in lung cancer and squamous cell carcinomas by other groups [21, 22], clearly indicating the important role of RND3 in tumorigenesis.…”

“…We also demonstrated that downregulation of RND3 promoted GBM cell proliferation and tumorigenesis [8]. …”

Knock-Down of Endogenous Bornavirus-Like Nucleoprotein 1 Inhibits Cell Growth and Induces Apoptosis in Human Oligodendroglia Cells

“…The role of RhoE in cancer is currently controversial [ 37 , 38 , 39 ]. In human glioblastoma, RND3 expression was found to be significantly decreased, which caused increased Notch-pathway activity and enhanced glioma cell proliferation [ 40 ]. RND3 functioned as a negative regulator of the Notch pathway by promoting the ubiquitination and degradation of Notch transcriptional complex [ 40 ].…”

“…In human glioblastoma, RND3 expression was found to be significantly decreased, which caused increased Notch-pathway activity and enhanced glioma cell proliferation [ 40 ]. RND3 functioned as a negative regulator of the Notch pathway by promoting the ubiquitination and degradation of Notch transcriptional complex [ 40 ]. In this study, RND3 was upregulated after EBLN1 silencing in OL cells, and MAML2 , coded a coactivator for Notch protein, was downregulated.…”

Retracted Article: MiR-182-5p and miR-96-5p increased hepatocellular carcinoma cell mobility, proliferation and cisplatin resistance partially by targeting RND3

“…The cell growth-inhibiting effect of RND3 overexpression has been demonstrated in esophageal squamous cell carcinoma cells, 23 while RND3 knockdown was found to enhance cell proliferation in glioblastoma cells and neural stem cells. 24,25 We therefore investigated whether miR-182-5p and miR-96-5p would inuence HCC cell growth in vitro by targeting RND3. Our cell viability and proliferation assay results both suggested that RND3 OE or TC-S 7001 treatment partially attenuated the cell proliferation-promoting effect of miR-182-5p or miR-96-5p agomir treatment in HCC cells in vitro (Fig.…”