LncRNA RP4-694A7.2 promotes non-small cell lung cancer proliferation by activating a YBX1-mediated DEPDC1/Wnt/β-catenin axis

Background Non-small cell lung cancer (NSCLC) is among the most prevalent malignancies; however, treatment options are limited owing to a paucity of effective therapeutic targets. Although long non-coding RNAs (lncRNAs) are critical regulators of tumor progression, their functional mechanisms and translational potential in NSCLC remain poorly understood. Patient-derived xenograft (PDX) models provide a clinically relevant platform for target discovery and therapeutic evaluation. Methods By integrating transcriptome screening of NSCLC PDX models with analysis of data from The Cancer Genome Atlas (TCGA), we identified lncRNA RP4-694A7.2 as a key oncogenic target. The expression and clinical relevance of RP4-694A7.2 were assessed using quantitative PCR with reverse transcription and fluorescence in situ hybridization assays. Functional roles were investigated through a series of in vitro assays (CCK-8, colony formation, EdU, and flow cytometry) and experiments using in vivo xenograft models. The underlying molecular mechanisms were dissected using RNA pull-down, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays. Finally, the therapeutic potential of RP4-694A7.2 was validated in NSCLC PDX models through intratumoral delivery of RP4-694A7.2-targeting small interfering RNAs. Results RP4-694A7.2 was markedly upregulated in NSCLC tissues and cells and promoted NSCLC proliferation by accelerating the G1/S phase transition. Mechanistically, RP4-694A7.2 directly bound to YBX1, suppressing WWP2-mediated K48-linked ubiquitination and proteasomal degradation, thereby enhancing YBX1 stability. Furthermore, RP4-694A7.2 strengthened the YBX1–KPNA2 interaction to facilitate YBX1 nuclear import. Nuclear-accumulated YBX1 subsequently bound to the DEPDC1 promoter to activate its transcription, leading to activation of the Wnt/β-catenin pathway and upregulation of c-Myc and cyclin D1. Notably, silencing of RP4-694A7.2 using small interfering RNAs markedly suppressed tumor growth in NSCLC PDX models. Conclusions Our findings show that RP4-694A7.2 promotes NSCLC proliferation through the YBX1/DEPDC1/Wnt/β-catenin axis, indicating that RP4-694A7.2 is a potential therapeutic target for this malignancy.