Abstract 2808: LUCAT1 facilitates areca nut-induced cell invasion and therapeutic resistance in head and neck cancer through STAT1 transcriptional modulation

Abstract Areca nut is a significant carcinogen associated with head and neck cancer (HNC) in Southeast Asia, but the mechanisms, particularly those involving long non-coding RNAs (lncRNAs), remain unclear. We previously identified the lncRNA LUCAT1 as induced by arecoline, a key areca nut component, and this study explores its crucial role in HNC progression. Silencing LUCAT1 reduced several arecoline-induced malignant features. These include cell invasion through epithelial-mesenchymal transition (EMT) modulation and chemo-radiotherapy resistance via reactive oxygen species (ROS) scavenging and autophagy regulation. RNA sequencing (RNA-seq) of LUCAT1-silenced cells revealed 2, 326 downstream effectors enriched in oncogenic pathways, including EGFR, VEGF, HIF-1, and extracellular matrix-receptor interactions. This underscored LUCAT1’s pivotal role in cell motility and survival. LUCAT1 predominantly localizes in the nucleus, suggesting transcriptional regulation. Bioinformatic analysis of its promoter revealed 491 transcription factors binding to a DNase hypersensitivity site (DHS). Integrative proteomic analysis of areca nut-treated HNC cells narrowed this to three key transcription factors (IRF6, CUX1, and STAT1). Among these, STAT1 was confirmed as the primary factor induced by arecoline to activate LUCAT1 transcription. Silencing STAT1 or inhibiting its phosphorylation using fludarabine suppressed LUCAT1 expression, reduced ROS-scavenging, and reversed arecoline-induced malignancy. Thus, this study demonstrates that areca nut upregulates LUCAT1 via STAT1 activation, contributing to cell invasion and therapeutic resistance in HNC. Additionally, fludarabine shows potential as a therapeutic agent to counteract areca nut-induced malignancy, offering a promising avenue to improve survival outcomes for HNC patients with areca nut-chewing. Citation Format: Hung-Han Huang, Ann-Joy Cheng. LUCAT1 facilitates areca nut-induced cell invasion and therapeutic resistance in head and neck cancer through STAT1 transcriptional modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2808.