RPUSD1 enhances the expression of eIF4E through RluA catalytic domain, activates PI3K/AKT signaling pathway, and promotes the cell proliferation and invasion in non-small cell lung cancer.

RNA pseudouridylate synthase domain containing 1 (RPUSD1) is a pseudouridine synthase, and its role in human solid tumors remains unknown. We found that RPUSD1 showed enhanced cytoplasmic expression in non-small cell lung cancer (NSCLC) using immunohistochemistry and western blotting. Its increased expression is associated with tumor malignant phenotypes. The RluA catalytic domain of RPUSD1 activated the phosphoinositide 3-kinase (PI3K)/ Protein Kinase B (AKT) pathway, which promoted cell proliferation, migration, and invasion. Following transfection with full-length RPUSD1, the eukaryotic translation initiation factor 4E (eIF4E) mRNA enrichment increased. Moreover, full-length RPUSD1 enhanced eIF4E and Nijmegen breakage syndrome protein 1 (NBS1) proteins, whereas RPUSD1-ΔRluA did not significantly enhance eIF4E and NBS1 proteins. Moreover, NBS1 overexpression increased binding between NBS1 and PI3K-p110, whereas PI3K-p110/PI3K-p85 binding was diminished. RPUSD1 is an oncogene in NSCLC. RPUSD1 binds to eIF4E mRNA and stabilizes eIF4E mRNA through its RluA catalytic domain. EIF4E increases NBS1 expression, promoting its binding to PI3K p110. It competitively inhibits the interaction of PI3K p110 with PI3K p85, which leads to the dissociation of PI3K p85 from PI3K p110. This dissociation increases PI3K activity and activates downstream AKT. Thus, it promotes the ability of cell proliferation, migration, and invasion in NSCLC.