A novel super-enhancer-driven lncRNA LINC00973 governs head and neck squamous cell carcinoma progression through EN2

Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators driving cancer development and potential therapeutic targets across multiple human malignancies. However, their mechanistic roles during head and neck squamous cell carcinoma (HNSCC) initiation and progression remain incompletely elucidated. Here, we identified a novel oncogenic lncRNA, LINC00973, which was aberrantly upregulated in clinical samples and associated with aggressive clinicopathological features and adverse clinical outcomes. LINC00973 promoted cell proliferation, migration, and invasion and inhibited cell apoptosis and senescence in vitro, and induced tumor growth and lymph node metastasis in vivo. Mechanistically, LINC00973 functioned as a molecular sponge for tumor-suppressive miR-6756-3p, consequently stabilizing transcription factor Engrailed-2 (EN2) mRNA and activating NOTCH pathway to promote HNSCC progression. Integrative epigenomics/transcriptomics analyses coupled with molecular assays revealed a proximal super-enhancer (SE) within the LINC00973 locus, which recruited Activator Protein 1 (AP-1)/FOS Like 1 (FOSL1), BRD4, and EP300, thereby collectively activating its transcription. CRISPR interference assay identified four functional enhancer elements of LINC00973-SE and H3K27ac HiChIP data analysis suggested enhancer-promoter contacts, collectively contributing to LINC00973 transcription. Clinically, the abundance of LINC00973, miR-6756-3p, EN2, and NOTCH1 in HNSCC samples was correlated and significantly associated with patients' survival. Collectively, our findings revealed a hitherto uncharacterized SE-driven LINC00973-miR-6756-3p-EN2 regulatory axis to facilitate HNSCC progression and highlighted LINC00973 as a promising prognostic biomarker and therapeutic target with considerable translational potential.