Rnf20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α [ChIP-Seq_P2t_Rnf20_Het_shHIF1A]

Defective DNA repair and metabolic rewiring are highly intertwined in promoting the development and progression of cancer. However, the molecular players at the interface of these processes remain largely unexplored. Here we show that the Rnf20-HIF1α axis links the DNA damage response and metabolic reprogramming in lung cancer. Haploinsufficiency of Rnf20, catalyzing histone H2B monoubiquitylation (H2Bub1), dramatically increases the occurrence of spontaneous lung adenocarcinoma and small cell lung carcinoma (SCLC) in mice. Mechanistically, ablation of a single Rnf20 allele resulted in insufficient Rnf20-H2Bub1-p53-mediated control and induced pronounced defects in DNA repair, increased cell growth, epithelial-to-mesenchymal transition (EMT), and metabolic rewiring via HIF1α-mediated RNA polymerase II promoter-proximal pause release, which was independent of H2Bub1. Importantly, RNF20 levels are decreased in lung adenocarcinoma and SCLC patients, and this decrease negatively correlates with the expression of HIF1α target genes, suggesting HIF1α inhibition as a promising therapeutic approach for lung cancer patients with decreased RNF20 activity.