title: Stabilization of the G-quadruplex at the VEGF IRES represses cap-independent translation.
abstract: The activation of translation contributes to malignant transformation and is an emerging target for cancer therapies. RNA G-quadruplex structures are general inhibitors of cap-dependent mRNA translation and were recently shown to be targeted for oncoprotein translational activation. In contrast however, the G-quadruplex within the 5'UTR of the human vascular endothelial growth factor A (VEGF) has been shown to be essential for IRES-mediated translation. Since VEGF has a pivotal role in tumor angiogenesis and is a major target of anti-tumoral therapies, we investigated the structure/function relationship of the VEGF G-quadruplex and defined whether it could have a therapeutic potential. We found that the G-quadruplex within the VEGF IRES is dispensable for cap-independent function and activation in stress conditions. However, stabilization of the VEGF G-quadruplex by increasing the G-stretches length or by replacing it with the one of NRAS results in strong inhibition of IRES-mediated translation of VEGF. We also demonstrate that G-quadruplex ligands stabilize the VEGF G-quadruplex and inhibit cap-independent translation in vitro. Importantly, the amount of human VEGF mRNA associated with polysomes decreases in the presence of a highly selective stabilizing G-quadruplex ligand, resulting in reduced VEGF protein expression. Together, our results uncover the existence of functionally silent G-quadruplex structures that are susceptible to conversion into efficient repressors of cap-independent mRNA translation. These findings have implications for the in vivo applications of G-quadruplex-targeting compounds and for anti-angiogenic therapies.
authors.affiliation: a Inserm UMR 1037- University of Toulouse III; Cancer Research Center of Toulouse (CRCT) ; Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Cammas
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dubrac
authors.forename: Benjamin
authors.initials: B
authors.lastname: Morel
authors.forename: Assala
authors.initials: A
authors.lastname: Lamaa
authors.forename: Christian
authors.initials: C
authors.lastname: Touriol
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Teulade-Fichou
authors.forename: Hervé
authors.initials: H
authors.lastname: Prats
authors.forename: Stefania
authors.initials: S
authors.lastname: Millevoi
mesh_terms: D020121:5' Untranslated Regions; D001483:Base Sequence; D054856:G-Quadruplexes; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D000067556:Internal Ribosome Entry Sites; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D000067556:Internal Ribosome Entry Sites; D008565:Membrane Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D008156:Luciferases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: G; G-quadruplex; IRES; UTR; VEGF; cap-independent; guanine; ligands; mRNA translation; untranslated region
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