A new IRES-mediated truncated Cx32 isoform inhibits global mRNA translation to suppress glioblastoma - 28/03/23
Abstract |
Glioblastoma (GBM) is the most lethal malignant primary brain tumor. Although multimodal therapy has been applied for GBM, the median survival time remains less than 16 months. Thus, better therapeutic targets in GBM are urgently needed. Herein, we first identified five new N-terminal-truncated Cx32 isoforms (GJB1–28k, GJB1–22k, GJB1–20k, GJB1–15k, and GJB1–13k) and further demonstrated that they were generated via cap-independent internal translation through internal ribosome entry sites (IRESs) in the coding sequence of GJB1 mRNA. Among these isoforms, GJB1–13k inhibited proliferation, promoted apoptosis, and limited cell cycle progression in GBM cells by inhibiting global mRNA translation. In vivo experiments further confirmed the antitumor activity of GJB1–13k against GBM cells. In addition, TSR3, a ribosomal maturation factor, was demonstrated to directly interact with GJB1–13k. Moreover, GBM cells with high TSR3 expression exhibited low sensitivity to GJB1–13k treatment, while GJB1–13k sensitivity was restored by TSR3 knockdown. Our work identifies a new IRES-mediated protein, GJB1–13k, and suggests that overexpression of GJB1–13k in GBM cells with low TSR3 expression or combined targeting of GJB1–13k and TSR3 in GBM cells with high TSR3 expression constitutes a potential therapeutic strategy for GBM.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
A new IRES-mediated truncated Cx32 isoform, GJB1−13k, inhibits global mRNA translation to suppress glioblastoma
A new IRES-mediated truncated Cx32 isoform, GJB1−13k, inhibits global mRNA translation to suppress glioblastomaga1Le texte complet de cet article est disponible en PDF.
Highlights |
• | 5 new Cx32 isoforms (GJB1−28k, −22k, −20k, −15k, and −13k) are generated via IRESs in GJB1 mRNA. |
• | GJB1−13k inhibits mRNA translation in, reduces proliferation of, promotes apoptosis in, and limits cell cycle progression in GBM cells. |
• | In vivo tests validated GJB1−13k’s antitumor efficacy against GBM cells. |
• | TSR3 interacts with GJB1−13k and impedes its anti-tumor function. |
Keywords : Glioblastoma, GJB1, IRES, GJB1–13k, mRNA translation
Abbreviations : GBM, IRESs, UTR, CDS, GJs, Cx43, RNA-seq, SUnSET, TSR3, RLuc, ORF, FLuc, CCK8, EdU, HA, IACUC, IHC, DEGs, KEGG, GO, GSEA, CPTAC, Co-IP, E. coli, CHX
Plan
Vol 161
Article 114513- mai 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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