D'Agostino Mattia, Rol-Moreno Javier, Bec Guillaume, Kuhn Lauriane, Ennifar Eric, Simonetti Angelita
Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, 2 Allée Konrad Roetgen, Strasbourg 67084, France.
Sanofi-Aventis R&D, Strasbourg 67000, France.
Nucleic Acids Res. 2025 Apr 22;53(8). doi: 10.1093/nar/gkaf321.
Tight regulation of translation initiation is crucial for cellular adaptation to environmental changes. Stress conditions like hypoxia trigger translational reprogramming of mRNAs encoding proteins essential for stress recovery and cell survival. Recent studies highlight alternative translation initiation pathways based on specific motifs in mRNA 5' untranslated regions (5'UTRs). Notably, β-catenin is of particular interest since maintaining its translation promotes cancer cell persistence and plasticity. β-Catenin, an oncogenic protein, plays a key role in Wnt signalling. Besides dysregulation of the β-catenin/Wnt pathway, chemotherapy-induced hypoxia leads to abnormal nuclear β-catenin accumulation, modulating gene expression linked to cancer progression and metastasis. However, the mechanism sustaining β-catenin translation in stressed cells remains elusive. To explore how β-catenin mRNA evades global translational blockade in hypoxic cancer cells, we analysed its 5'UTR and identified a translation regulatory element in cellulo. We discovered a GC-rich three-way junction (TWJ) structure within the β-catenin 5'UTR enhancing its hypoxia-driven translation. A polypurine region within the TWJ anchors eIF4B, eIF4A, and eIF4G2. Importantly, the TWJ makes β-catenin mRNA translation eIF4A-dependent and sensitive to silvestrol, a selective eIF4A inhibitor and promising anticancer agent. This study elucidates the 5'UTR-driven β-catenin mechanism under hypoxia, paving the way to inhibit its translation in cancer.
翻译起始的严格调控对于细胞适应环境变化至关重要。低氧等应激条件会引发对编码应激恢复和细胞存活所必需蛋白质的mRNA进行翻译重编程。最近的研究强调了基于mRNA 5'非翻译区（5'UTR）中特定基序的替代翻译起始途径。值得注意的是，β-连环蛋白特别受关注，因为维持其翻译会促进癌细胞的持久性和可塑性。β-连环蛋白是一种致癌蛋白，在Wnt信号传导中起关键作用。除了β-连环蛋白/Wnt途径失调外，化疗诱导的低氧还会导致细胞核β-连环蛋白异常积累，调节与癌症进展和转移相关的基因表达。然而，应激细胞中维持β-连环蛋白翻译的机制仍然不清楚。为了探究β-连环蛋白mRNA如何在低氧癌细胞中逃避整体翻译阻滞，我们分析了其5'UTR并在细胞内鉴定出一个翻译调控元件。我们在β-连环蛋白5'UTR内发现了一个富含GC的三向接头（TWJ）结构，可增强其低氧驱动的翻译。TWJ内的一个聚嘌呤区域锚定eIF4B、eIF4A和eIF4G2。重要的是，TWJ使β-连环蛋白mRNA翻译依赖于eIF4A，并对silvestrol敏感，silvestrol是一种选择性eIF4A抑制剂和有前景的抗癌药物。这项研究阐明了低氧条件下5'UTR驱动的β-连环蛋白机制，为在癌症中抑制其翻译铺平了道路。
