Translational Regulation by hnRNP H/F Is Essential for the Proliferation and Survival of Glioblastoma.
Morgane Le BrasNoah GorelickSylvain PautetBetty M TylerStéphane ManentiNicolas SkuliStefania MillevoiAnne CammasPublished in: Cancers (2022)
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.
Keyphrases
- signaling pathway
- pi k akt
- induced apoptosis
- cell cycle arrest
- epithelial mesenchymal transition
- nucleic acid
- binding protein
- poor prognosis
- oxidative stress
- cell proliferation
- type diabetes
- squamous cell carcinoma
- sensitive detection
- transcription factor
- long non coding rna
- protein kinase
- stem cells
- adipose tissue
- cancer therapy
- bone marrow
- skeletal muscle
- smoking cessation