RNF20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α

Hao Liu, Yongqin Tang, Anshu Singh, Joaquim Vong, Julio Cordero, Arthur Mathes, Rui Gao, Yanhan Jia, Boyan K. Garvalov, Till Acker, Gernot Poschet, Rüdiger Hell, Marc A. Schneider, Joerg Heineke, Thomas Wieland, Guillermo Barreto, Adelheid Cerwenka, Michael Potente, Sofia-Iris Bibli, Rajkumar Savai and Gergana Dobreva ()
Additional contact information
Hao Liu: Heidelberg University
Yongqin Tang: Heidelberg University
Anshu Singh: Heidelberg University
Joaquim Vong: Max Planck Institute for Heart and Lung Research
Julio Cordero: Heidelberg University
Arthur Mathes: Heidelberg University
Rui Gao: Heidelberg University
Yanhan Jia: Heidelberg University
Boyan K. Garvalov: Heidelberg University
Till Acker: Justus Liebig University
Gernot Poschet: Heidelberg University
Rüdiger Hell: Heidelberg University
Marc A. Schneider: German Center for Lung Research (DZL)
Joerg Heineke: Heidelberg University
Thomas Wieland: German Centre for Cardiovascular Research (DZHK)
Guillermo Barreto: UMR
Adelheid Cerwenka: Heidelberg University
Michael Potente: Max Planck Institute for Heart and Lung Research
Sofia-Iris Bibli: Goethe University
Rajkumar Savai: Justus Liebig University
Gergana Dobreva: Heidelberg University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60223-4

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