An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene.
journal contributionposted on 2023-06-08, 11:23 authored by Muhammad S Azman, Emilie L Alard, Martin Dodel, Federica Capraro, Rupert Faraway, Maria Dermit, Wanling Fan, Alina Chakraborty, Jernej Ule, Faraz K Mardakheh
Oncogenic RAS signaling reprograms gene expression through both transcriptional and post-transcriptional mechanisms. While transcriptional regulation downstream of RAS is relatively well characterized, how RAS post-transcriptionally modulates gene expression to promote malignancy remains largely unclear. Using quantitative RNA interactome capture analysis, we here reveal that oncogenic RAS signaling reshapes the RNA-bound proteomic landscape of pancreatic cancer cells, with a network of nuclear proteins centered around nucleolin displaying enhanced RNA-binding activity. We show that nucleolin is phosphorylated downstream of RAS, which increases its binding to pre-ribosomal RNA (rRNA), boosts rRNA production, and promotes ribosome biogenesis. This nucleolin-dependent enhancement of ribosome biogenesis is crucial for RAS-induced pancreatic cancer cell proliferation and can be targeted therapeutically to inhibit tumor growth. Our results reveal that oncogenic RAS signaling drives ribosome biogenesis by regulating the RNA-binding activity of nucleolin and highlight a crucial role for this mechanism in RAS-mediated tumorigenesis.
Nucleolinpancreatic ductal adenocarcinomaRASribosome biogenesisRNA-binding proteinsHumansGenes, rasMAP Kinase Signaling SystemProteomicsPhosphoproteinsRNA, RibosomalRNACell Transformation, NeoplasticRibosomesPancreatic NeoplasmsUle - sec06 Biological Sciences08 Information and Computing Sciences11 Medical and Health SciencesDevelopmental Biology