An ERK1/2‐driven RNA‐binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene

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.