Fiche publication
Date publication
mai 2025
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BARRETO Guillermo
Tous les auteurs :
Liu H, Tang Y, Singh A, Vong J, Cordero J, Mathes A, Gao R, Jia Y, Garvalov BK, Acker T, Poschet G, Hell R, Schneider MA, Heineke J, Wieland T, Barreto G, Cerwenka A, Potente M, Bibli SI, Savai R, Dobreva G
Lien Pubmed
Résumé
Defective DNA repair and metabolic rewiring are highly intertwined in promoting the development and progression of cancer. However, the molecular players at their interface remain poorly understood. Here we show that an RNF20-HIF1α axis links the DNA damage response and metabolic reprogramming in lung cancer. We demonstrate that RNF20, which catalyzes monoubiquitylation of histone H2B (H2Bub1), controls Rbx1 expression and thereby the activity of the VHL ubiquitin ligase complex and HIF1α levels. Ablation of a single Rnf20 allele significantly increases the incidence of lung tumors in mice. Mechanistically, Rnf20 haploinsufficiency results in inadequate tumor suppression via the Rnf20-H2Bub1-p53 axis and induces DNA damage, cell growth, epithelial-mesenchymal transition (EMT), and metabolic rewiring through HIF1α-mediated RNA polymerase II promoter-proximal pause release, which is independent of H2Bub1. Importantly, decreased RNF20 levels correlate with increased expression of HIF1α and its target genes, suggesting HIF1α inhibition as a promising therapeutic approach for lung cancer patients with reduced RNF20 activity.
Mots clés
Hypoxia-Inducible Factor 1, alpha Subunit, metabolism, Animals, Ubiquitin-Protein Ligases, metabolism, Lung Neoplasms, metabolism, Humans, Mice, DNA Damage, Histones, metabolism, Epithelial-Mesenchymal Transition, genetics, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Mice, Knockout, Tumor Suppressor Protein p53, metabolism, DNA Repair, Von Hippel-Lindau Tumor Suppressor Protein, metabolism, Ubiquitination, Female, Male, RNA Polymerase II, metabolism
Référence
Nat Commun. 2025 05 28;16(1):4929
