LncRNA RAMS11-dependent NOTCH3 activation drives tumor progression in non-small cell lung cancer

Lung cancer is currently the leading cause of cancer-related deaths worldwide. Approximately 85% of lung cancer patients have non-small cell lung cancer (NSCLC), and >50% of these patients present with metastasis at their initial diagnosis. Despite advances in our understanding of lung cancer oncogenesis, the mechanism by which lung cancer becomes aggressive and leads to patient death is still poorly characterized. We found that long noncoding RNA RNA-associated with metastasis 11 (RAMS11) (LINC01564) is significantly upregulated in lung cancer patients compared to healthy patients. Here, we demonstrate that RAMS11 is critical for NSCLC tumor progression by regulating expression of NOTCH3, a key driver of tumorigenic potential. Mechanistically, RAMS11 is essential for NRF2 chromatin binding and the associated deposition of the active enhancer mark, H3K27ac, at the NOTCH3 enhancer region. Functional analysis revealed RAMS11-NRF2-dependent activation of NOTCH3 signaling enforces a tumor-initiating capacity, characterized by enhanced self-renewal capabilities and tumor initiation ability, thereby supporting malignant proliferation. Moreover, disruption of RAMS11 signaling markedly suppressed tumorigenic growth and sensitized NSCLC cells to cisplatin-induced apoptosis, uncovering a potential therapeutic vulnerability to more effectively target NSCLC patients. Collectively, these findings reveal a previously unknown role of RAMS11 in NSCLC progression and chemotherapy resistance.