LUCAT1 Drives Arecoline-Induced Head and Neck Cancer Progression via STAT1-Mediated Transcriptional Regulation

Background: Areca nut chewing is a major environmental risk factor for head and neck cancer (HNC), particularly in Southeast Asia. However, the molecular mechanisms that link areca nut exposure to malignant progression remain poorly understood. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of oncogenesis, but their role in areca nut-associated HNC remains unexplored. Methods: We performed functional assays, transcriptomic profiling, and bioinformatic analyses to investigate the role of the lncRNA LUCAT1 in arecoline-treated HNC cells. Cell motility, epithelial–mesenchymal transition (EMT), reactive oxygen species (ROS) levels, and therapeutic resistance were assessed following LUCAT1 knockdown or overexpression. We identified upstream regulators of LUCAT1 through promoter analysis, transcription factor knockdown, and pharmacological inhibition. Results: LUCAT1 expression was significantly upregulated by arecoline exposure and promoted cell motility, EMT, ROS clearance, and resistance to radiotherapy and chemotherapy. Knockdown of LUCAT1 reversed these malignant phenotypes and suppressed antioxidant enzyme expression, partly through modulation of the p38 MAPK pathway. Transcriptomic and promoter analyses identified STAT1 as a key transcription factor activated by arecoline through muscarinic acetylcholine receptor (mAChR) signaling. Functional rescue experiments confirmed that LUCAT1 acts downstream of STAT1 to sustain arecoline-induced tumor aggressiveness. Conclusion: Our findings define a novel mAChR–STAT1–LUCAT1 regulatory axis that mediates areca nut-induced malignant progression in HNC. This study not only reveals a critical molecular pathway linking environmental carcinogen exposure to oncogenic transcriptional reprogramming but also highlights LUCAT1 as a promising target for therapeutic intervention in high-risk HNC patients.