UBE2C induces EMT through Wnt/β-catenin and PI3K/Akt signaling pathways by regulating phosphorylation levels of Aurora-A

Abstract

The ubiquitin-conjugating enzyme 2C (UBE2C) is the key component in the ubiquitin proteasome system (UPS) by partnering with the anaphase-promoting complex (APC/C). A high UBE2C protein expression level has been reported in various types of human tumors. However, little is known about the precise mechanism by which UBE2C expression is downregulated in gastric cancer. We found in MGC-803 and SGC-7901 gastric cancer cells UBE2C-deficient G2/M phase arrest in the cell cycle and subsequently decreased gastric adenocarcinoma tumorigenesis. In the previous study, we identified Aurora-A (AURKA) as the hub gene of the gastric cancer linkage network based genome-wide association study (eGWAS). Furthermore, knockdown of UBE2C using siRNA markedly reduced the level of phosphorylation AURKA (p-AURKA) via Wnt/β-catenin and PI3K/Akt signaling pathways suppressed the occurrence and development of gastric cancer. Additionally, the expression of E-cadherin was up-regulated and N-cadherin was down-regulated in response to UBE2C knockdown and inhibits epithelial-mesenchymal transition (EMT). Collectively, our data suggest that the activity of AURKA might be regulated by UBE2C through regulating the activity of APC/C. UBE2C may be a new marker in the diagnosis of gastric cancer and may be a potential therapeutic target for the treatment of gastric adenocarcinoma.

<p>UBE2O Promotes Progression and Epithelial–Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma</p>

“…41 In addition, UBE2C knockdown impeded EMT by repressing the phosphorylation of the hub oncogenic gene Aurora-A in gastric adenocarcinoma. 32 In this study, our data revealed that UBE2O could potentiate TGF-β1-induced EMT, leading to enhanced proliferation, motility and metastatic capacity in HNSCC cells. Interestingly, Zhang et al reported that UBE2O promoted the monoubiquitination of inhibitory Smad6 and therefore facilitated adipogenesis induced by BMP7; 10 these findings indicated that UBE2O could skew the balance of the Smad-dependent signaling pathways toward a stimulatory status via the inactivation of inhibitory Smads, including Smad6/7.…”

“…30,31 For instance, UBE2C is overexpressed in diverse human cancers and promotes malignant tumor progression through the activation of multiple oncogenic signaling pathways, including Wnt/β-catenin, Erk and PI3K/Akt pathways. [32][33][34] However, the function of UBE2O still remains unknown. UBE2O was first purified from rabbit reticulocytes and considered an E2 enzyme due to its specific and conserved ubiquitin-conjugating domain.…”

The Association Between AURKA Gene rs2273535 Polymorphism and Gastric Cancer Risk in a Chinese Population

“…The overexpression of CCNB1 ( Begnami et al, 2010 ) and TPX2 ( Tomii et al, 2017 ) have been demonstrated to be associated with poor survival in Gc. Further, UBE2C induced epithelial-mesenchymal transition (EMT) by regulating phosphorylation levels of AURKA ( Wang et al, 2017 ). Therefore, we hypothesized that AURKA was related to poor survival of GC.…”

MicroRNA-based regulation of Aurora A kinase in breast cancer

“…Studies have shown that AURKA is involved in multiple mechanisms-associated with cancer initiation [51]. AURKA overexpression was also suggested to increase the expression of MMP-2, MMP-7, MMP-9, leading to tumor metastasis by degrading extracellular matrix proteins [52][53][54]. Zhong et al [55] identified AURKA as potential therapeutic targets in glioblastoma-bearing rats.…”