Translational Regulation by hnRNP H/F Is Essential for the Proliferation and Survival of Glioblastoma

Author:

Le Bras Morgane,Gorelick NoahORCID,Pautet Sylvain,Tyler BettyORCID,Manenti Stéphane,Skuli Nicolas,Millevoi Stefania,Cammas Anne

Abstract

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.

Funder

Institut National de la Santé et de la Recherche Médicale

Agence Nationale de la Recherche

Association pour la Recherche sur le Cancer

Emergence Cancéropole GSO

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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