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

Author

Listed:
  • Hao Liu

    (Heidelberg University)

  • Yongqin Tang

    (Heidelberg University)

  • Anshu Singh

    (Heidelberg University
    Max Planck Institute for Heart and Lung Research)

  • Joaquim Vong

    (Max Planck Institute for Heart and Lung Research)

  • Julio Cordero

    (Heidelberg University)

  • Arthur Mathes

    (Heidelberg University)

  • Rui Gao

    (Heidelberg University
    Max Planck Institute for Heart and Lung Research)

  • Yanhan Jia

    (Heidelberg University
    Max Planck Institute for Heart and Lung Research)

  • 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)
    Thoraxklinik at Heidelberg University Hospital)

  • Joerg Heineke

    (Heidelberg University
    German Centre for Cardiovascular Research (DZHK))

  • Thomas Wieland

    (German Centre for Cardiovascular Research (DZHK)
    Heidelberg University)

  • Guillermo Barreto

    (UMR)

  • Adelheid Cerwenka

    (Heidelberg University
    Heidelberg University)

  • Michael Potente

    (Max Planck Institute for Heart and Lung Research
    Berlin Institute of Health at Charité -Universitätsmedizin Berlin
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Sofia-Iris Bibli

    (Goethe University
    Heidelberg University)

  • Rajkumar Savai

    (Justus Liebig University
    Member of the Cardio-Pulmonary Institute (CPI))

  • Gergana Dobreva

    (Heidelberg University
    Max Planck Institute for Heart and Lung Research
    Goethe University
    Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University)

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.

Suggested Citation

  • 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 , 2025. "RNF20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60223-4
    DOI: 10.1038/s41467-025-60223-4
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