CUEDC2 suppresses glioma tumorigenicity by inhibiting the activation of STAT3 and NF-κB signaling pathway

Abstract

CUEDC2, a CUE domain containing 2 protein, plays critical roles in many biological processes, such as cell cycle, inflammation and tumorigenesis. However, whether CUEDC2 was involved in tumorigenesis of glioma and the possible mechanism remains to be elucidated. In the present study, our results implied that the expression of CUEDC2 was lower in the glioma tissue and glioma cell lines than that of normal tissue and asctrocyte cells. Downregulation of endogenous CUEDC2 in glioma U251 cell lines by RNAi promoted the tumor cells proliferation, migration, invasion and glioma neurosphere formation, while, overexpression of CUEDC2 showed the opposite effect. Further studies showed that overexpression of CUEDC2 suppressed the activation and nuclear translocation of phosphorylated-STAT3 (p-STAT3) but the level of p-STAT3 increased after interfering with the expression of CUEDC2. Moreover, CUEDC2 expression has an inhibitory effect on the activation of NF-κB. Thus, our studies suggested that the decreased expression of CUEDC2 in glioma led to the activation of transcription factor STAT3 and NF-κB signaling pathway which may be related to the tumorigenicity in glioma.

RIOK2 is negatively regulated by miR‐4744 and promotes glioma cell migration/invasion through epithelial‐mesenchymal transition

“…A Transwell system with a polycarbonate filter membrane was used to perform cell migration and invasion assays as described in the literature 26,27 . Briefly, cells were seeded at a density of 1 × 10 4 cells in 200 µL of serum‐free medium in the upper chamber.…”

Disruption of gene SPL35, encoding a novel CUE domain‐containing protein, leads to cell death and enhanced disease response in rice

“…Recognition of ubiquitin or specific ubiquitin chains by ubiquitin-binding domains (UBDs) is vital for deciphering ubiquitin-mediated signalling pathways . Among a handful of types of characterized UBDs, the coupling of ubiquitin conjugation to endoplasmic reticulum (ER) degradation (CUE) domains consisting of 42-43 amino acid sequences have been identified and characterized based on similarity to the region of the yeast Cue1 protein, which is implicated in yeast ER-associated degradation (ERAD; Shih et al, 2003); however, their roles in ERAD remain poorly understood (Li et al, 2017;Liu et al, 2012a;Shideler et al, 2015). In animals, some CUE domain-containing (CUEDC) proteins have been implicated in programmed cell death (PCD) and immunity.…”

“…In animals, some CUE domain-containing (CUEDC) proteins have been implicated in programmed cell death (PCD) and immunity. For examples, the CUEDC protein, ERAD E3 gp78, is a regulator of liver homeostasis and a tumour suppressor in liver, and its CUE domain interacts with ubiquitin and diubiquitin and functions to facilitate substrate binding and processivity in ubiquitination Zhang et al, 2015); another CUEDC protein, CUEDC2, suppresses glioma tumorigenicity by inhibiting the activation of STAT3 and NF-jB, and its CUE domain is essential for functional interactions with both monoubiquitin and polyubiquitin (Li et al, 2017). In plants, the reported CUECD proteins are the duplicated pair of Arabidopsis RING-finger E3 ligases, RIN2 and RIN3, which each possess a RING-finger domain in association with a CUE domain; however, the CUE domain was rarely characterized for its roles in the E3 ligases (Kawasaki et al, 2005).…”

Molecular Determinants of Malignant Brain Cancers: From Intracellular Alterations to Invasion Mediated by Extracellular Vesicles

“…Recently, it was found, for example, which netrin-1, a protein probably involved in axon guidance during brain development, is highly expressed in glioma cells, in a tumor grade-dependent way; it was suggested that netrin-1 activates NF-κB in an Unc5 netrin receptor A-dependent route, resulting in increased c-Myc expression [ 123 ]. Another study suggested that NF-κB and JAK1-STAT3 pathways can be activated by CUE domain-containing protein 2 (CUED2), influencing glioma development [ 124 ]. One consequence of the activation of NF-κB but also of other transcription factors (e.g., AP-1 and Sp1), which are downstream to the mitogen-activated protein kinase (MAPK) and PI3/Akt pathways, is that they might enhance the expression of MMPs [ 125 , 126 ] and of some of the transporters related to glycolytic metabolism, such as GLUT3 [ 127 ].…”