Abstract
Simple SummaryDeveloping effective treatments for glioblastoma (GBM), a highly aggressive brain tumor that is resistant to current therapies, is an urgent medical need that can be addressed by the in-depth study of basic biology for the identification of relevant targets. The aim of the present study was to investigate the molecular mechanisms underlying the deregulation of protein synthesis associated with GBM progression and resistance to treatments. Our present work demonstrates the role of the RNA-binding proteins hnRNP H/F as key players in the control of protein synthesis in GBM through different overlapping mechanisms. Furthermore, our results show that hnRNP H/F potentiate cellular processes underlying the aggressive and resistant phenotype of GBMs, thus indicating hnRNP H/F as a potential target for therapeutic intervention.Deregulation of mRNA translation is a widespread characteristic of glioblastoma (GBM), aggressive malignant brain tumors that are resistant to conventional therapies. RNA-binding proteins (RBPs) play a critical role in translational regulation, yet the mechanisms and impact of these regulations on cancer development, progression and response to therapy remain to be fully understood. Here, we showed that hnRNP H/F RBPs are potent regulators of translation through several mechanisms that converge to modulate the expression and/or the activity of translation initiation factors. Among these, hnRNP H/F regulate the phosphorylation of eIF4E and its translational targets by controlling RNA splicing of the A-Raf kinase mRNA, which in turn modulates the MEK-ERK/MAPK signaling pathway. The underlying mechanism involves RNA G-quadruplex (RG4s), RNA structures whose modulation phenocopies hnRNP H/F translation regulation in GBM cells. Our results highlighted that hnRNP H/F are essential for key functional pathways regulating proliferation and survival of GBM, highlighting its targeting as a promising strategy for improving therapeutic outcomes.
Highlights
Glioblastoma (GBM) is a grade IV brain tumor, which is one of the most aggressive primary brain tumors in humans [1]
Our results showed that hnRNP H/F depletion significantly inhibited the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) on serine 209, while leaving the expression of total eIF4E
Similar results were observed in U87 and U251 (Figure S1F) GBM cells, indicating that the effects of hnRNP H/F on this signaling pathway were not cell-type-specific effects. These results suggest that hnRNP H/Fmediated control of A-Raf splicing in GBM cells increases eIF4E phosphorylation, possibly impacting on its function in translational regulation
Summary
Glioblastoma (GBM) is a grade IV brain tumor, which is one of the most aggressive primary brain tumors in humans [1]. Despite the current standard of care, combining surgical resection with radiotherapy and concomitant/adjuvant chemotherapy with temozolomide (TMZ), the prognosis of patients with GBM remains poor, with a median survival of 14–15 months [2,3] This dismal outcome is mainly due to a high rate of tumor recurrence linked to the characteristic heterogeneous population of cells that are genetically unstable, highly infiltrative and resistant to conventional treatments [4]. In this context, the still incomplete understanding of the basic biology of GBM needs to be investigated to identify new targets and develop novel therapeutic strategies to fill this major unmet clinical need in oncology. There is evidence that the expression and/or activity of translation regulators—such as eukaryotic translation initiation factors (eIFs) or RNA-binding proteins (RBPs)—are modified in cancer [11–14]
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