Uev1A promotes breast cancer cell migration by up-regulating CT45A expression via the AKT pathway

Tong Niu,Zhaojia Wu,Wei Xiao

doi:10.1186/s12885-021-08750-3

Abstract

BackgroundUEV1A encodes a ubiquitin-E2 variant closely associated with tumorigenesis and metastasis, but its underlying mechanism in promoting metastasis remains to be investigated.MethodsIn this study, we experimentally manipulated UEV1A and CT45A gene expression and monitored their effects on cancer-related gene expression, cell migration and the signal transduction cascade.ResultsIt was found that UEV1A overexpression induces CT45A family gene expression in breast cancer cells. Indeed, ectopic expression of UEV1A was sufficient to induce CT45A and its downstream genes involved in tumorigenesis, epithelial-mesenchymal transition (EMT), stemness and metastasis, and to promote cell migration and EMT signaling. Consistently, depletion of CT45A abolished the above effects, indicating that CT45A is a critical downstream effector of Uev1A. The Uev1A-induced cell migration and EMT signaling was dependent on AKT but independent of NF-κB, indicating that CT45A acts downstream of the AKT pathway.ConclusionsBased on previous reports and observations in this study, we propose that the Ubc13-Uev1A complex activates AKT through K63-linked polyubiquitination, which leads to enhanced CT45A expression, stimulated cell migration and EMT signaling in breast cells. Since similar effects were also observed in a colorectal cancer cell line, the Ubc13/Uev1A-AKT-CT45A axis may also promote tumorigenesis and metastasis in other tissues.

Highlights

UEV1A encodes a ubiquitin-E2 variant closely associated with tumorigenesis and metastasis, but its underlying mechanism in promoting metastasis remains to be investigated
Since similar effects were observed in a colorectal cancer cell line, the Uev1A/Ubc13-Protein kinase B (AKT)-CT45A axis in tumorigenesis may occur in other tissues
To independently examine the role of Uev1A in upregulating CT45A expression and its biological implications, UEV1A was cloned into a pcDNA4.0/TO/HA(+) vector and transiently trasfected into MDA-MB-231 and MCF7 cells

Summary

Introduction

UEV1A encodes a ubiquitin-E2 variant closely associated with tumorigenesis and metastasis, but its underlying mechanism in promoting metastasis remains to be investigated. Ubiquitin (Ub)-conjugating enzyme variant (UEV, including Mms and Uev in mammalian cells) is a co-factor of Ubc13 [13] and absolutely required for. At least three UEV1 splicing variants have been reported, among which Uev1A and Uev1C could promote K63-linked polyubiquitination by forming a complex with Ubc, whereas Uev1B could not [18]. Despite the fact that Uev1A and Mms are two major Uevs in mammalian cells and share a similar biochemical activity, they appear to function differently: Ubc13Mms is required for DNA-damage response, whereas Ubc13-Uev1A is involved in NF-κB activation [18] and AKT activation [6]. Previous studies demonstrated that Uev1A-Ubc represses stress-induced apoptosis in

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