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

Abstract

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. image Oncogenic RAS‐induced ERK1/2 activity promotes the phosphorylation and RNA‐binding activity of nucleolin (NCL), boosting ribosome biogenesis, protein synthesis, and pancreatic tumorigenesis. Oncogenic KRAS reshapes the RNA‐bound proteomic landscape of pancreatic ductal adenocarcinoma cells, increasing the activity of RNA‐binding proteins, including NCL. NCL is phosphorylated downstream of oncogenic KRAS, via ERK1/2‐mediated activation of casein kinase 2, enhancing its binding to pre‐rRNA. Increased NCL–pre‐rRNA binding boosts nascent pre‐rRNA levels, leading to increased ribosome biogenesis and protein synthesis. NCL‐promoted ribosome biogenesis is required for KRAS‐driven tumorigenesis and can be therapeutically exploited.