Abstract
Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor. E3 ligases play important functions in glioma pathogenesis. CRISPR system offers a powerful platform for genome manipulation, while the screen of E3 ligases in GBM still remains to be explored. Here, we first constructed an E3 ligase small guide RNA (sgRNAs) library for glioma cells growth screening. After four passages, 299 significantly enriched or lost genes (SELGs) were compared with the initial state. Then the clinical significance of SELGs were validated and analyzed with TCGA glioblastoma and CGGA datasets. As RNF185 showed lost signal, decreased expression and favorable prognostic significance, we chose RNF185 for functional analysis. In vitro overexpressed cellular phenotype showed that RNF185 was a tumor suppressor in two glioma cell lines. Finally, the molecular mechanism of decreased RNF185 expression was investigated and increased miR-587 expression and DNA hypermethylation was evaluated. This study would provide a link between the molecular basis and glioblastoma pathogenesis, and a novel perspective for glioblastoma treatment.
Highlights
Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor, categorized as grade IV diffuse glioma by the World Health Organization (WHO) [1,2,3,4]
E3 ubiquitin ligases library Clustered regularly interspaced short palindromic repeats (CRISPR) screening reveals glioma cell growth regulators To explore the function of E3 ubiquitin ligases on tumor growth phenotype of glioma, a sgRNAs library of 557 E3 ligase genes were constructed, and followed by lentivirus packaging
The sgRNAs sequences of 557 E3 ubiquitin ligases and analyzed results were shown in Additional file 1: Table S1
Summary
Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor, categorized as grade IV diffuse glioma by the World Health Organization (WHO) [1,2,3,4]. The ubiquitin–proteasome system regulates many cellular processes, including cell cycle, differentiation, DNA repair, and the immune response in cancer [13]. Accumulating evidence shows that E3 ligases play important functions in glioma pathogenesis, progression, therapy response and prognostic marker [14]. Cullin-7 (CUL7) plays a significant role in promoting gliomagenesis via NF-κB activation [15]. FBXO16, a component of SCF E3 ubiquitin ligase complex has been proved to mediateβ-catenin degradation, and its attenuation could activate Wnt signaling and promote glioblastoma [16]. The ubiquitin–proteasome system and E3 ligases have been proposed as therapeutic targets in cancers, including glioma [17, 18]. Thereby, reveals the role of E3 ligases in glioblastoma would provide novel targets for the therapy of glioma
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