UBE2T promotes glioblastoma invasion and migration via stabilizing GRP78 and regulating EMT.

Peng Huang,Zitong Zhao,Yuduo Guo,Yongmei Song,Mingshan Zhang,Chunyu Gu,Hongwei Zhang,Weihai Ning,Haoran Wang,Yanming Qu

doi:10.18632/aging.103239

Abstract

Glioblastoma (GBM) generally has a dismal prognosis, and it is associated with a poor quality of life as the disease progresses. However, the development of effective therapies for GBM has been deficient. Ubiquitin-conjugating enzyme E2T (UBE2T) is a member of the E2 family in the ubiquitin-proteasome pathway and a vital regulator of tumour progression, but its role in GBM is unclear. In this study, we aimed to clarify the role of UBE2T in GBM. Bioinformatics analysis identified UBE2T as an independent risk factor for gliomas. Immunohistochemistry was used to measure UBE2T expression in GBM and normal tissue samples obtained from patients with GBM. The effects of UBE2T on GBM cell invasion and migration were analysed using the Transwell assay. BALB/c nude mice were used for the in vivo assays. Immunoblotting and immunoprecipitation were performed to determine the molecular mechanisms. UBE2T was highly expressed in GBM tissues, and its expression was linked to a poor prognosis. In vitro, depletion of UBE2T significantly suppressed cell invasion and migration. Moreover, UBE2T depletion suppressed the growth of GBM subcutaneous tumours in vivo. Further experiments revealed that UBE2T suppressed invasion and migration by regulating epithelial- mesenchymal transition (EMT) via stabilising GRP78 in GBM cells. We uncovered a novel UBE2T/GRP78/EMT regulatory axis that modulates the malignant progression and recurrence of GBM, indicating that the axis might be a valuable therapeutic target.

Highlights

Malignant gliomas are the most common fatal brain tumours
We formulated some standards to screen candidate genes. (I): First, we examined the RNA sequencing data of glioma and normal brain tissues from the the Chinese Glioma Genome Atlas (CGGA) and Genotype-Tissue Expression Project (GTEx) databases
Batch normalisation and normalisation of the expression profiles, 4007 differentially expressed genes (DEGs) involved in recurrent GBM and 4388 DEGs involved in primary

Summary

Introduction

Glioblastoma (GBM), the most aggressive glioma, is associated with a dismal prognosis and poor quality of life, as well as an average survival of 10–14 months after diagnosis over the last 5 years [1, 2]. The survival of patients with GBM remains poor despite standard surgery, radiation and chemotherapy [5]. Large-scale genome-wide profiling studies yielded an abundance of genome data and provided deeper insights into the molecular pathogenesis of glioma [2, 6]. This increased understanding of the genetic and pathogenic mechanisms of GBM has stimulated the development of novel therapeutic strategies, including the use of molecular targeted agents [7, 8]. The DNA-alkylating agent temozolomide (TMZ) in combination with www.aging-us.com radiotherapy has displayed a good therapeutic effect in patients with tumours displaying promoter methylation of the DNA repair enzyme O6-methylguanine-DNA methyl transferase [2, 9, 10]

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