Dual-compartment engagement of STAR-family proteins SAM68 and QKI by LINC00941 sustains oncogenic fitness in RAS-driven lung cancer

Abstract

Long non-coding RNAs (lncRNAs) are increasingly recognised as effectors of oncogenic signalling, yet the transcriptional programmes through which driver mutations regulate lncRNA expression remain poorly defined. Here we identify LINC00941 as a direct transcriptional target of FOSL1, an AP-1 transcription factor downstream of the KRAS-MAPK pathway, establishing the first FOSL1-regulated lncRNA in lung adenocarcinoma (LUAD). LINC00941 is significantly upregulated in LUAD across multiple independent cohorts, and its depletion via siRNAs, shRNAs, and antisense oligonucleotides (ASOs) induces proliferative arrest and stress-induced premature senescence, accompanied by transcriptomic suppression of cell cycle and DNA damage response (DDR) genes. Mechanistically, LINC00941 operates through a dual-compartment mechanism engaging two STAR-family RNA-binding proteins in distinct subcellular contexts. In the nucleus, LINC00941 binds SAM68 through its 700-1300 nucleotide region and shields it from proteasomemediated degradation, thereby sustaining SAM68-dependent PARP1 activation and DDR competency; RNF123 is identified as a candidate E3 ligase mediating SAM68 turnover in the absence of LINC00941. In the cytoplasm, LINC00941 sequesters QKI, preventing its nuclear translocation; LINC00941 depletion releases QKI to the nucleus, driving alternative splicing dysregulation including validated NUMB exon 12 exclusion, and QKI co-depletion rescues the anti-proliferative phenotype both in vitro and in xenograft models. Multi-cohort survival analysis across three independent LUAD datasets (n=649) identifies LINC00941 as an independent prognostic factor for poor overall survival. Gymnotic ASO-mediated targeting of LINC00941 significantly suppresses xenograft tumour growth without systemic toxicity, providing preclinical proof-of-concept for therapeutic tractability. Together, these findings establish LINC00941 as a compartment-specific oncogenic scaffold within the KRAS-FOSL1 transcriptional axis and a tractable therapeutic target in LUAD.