Abstract
INTRODUCTION: Metastatic recurrence drives dismal survival in esophageal squamous cell carcinoma (ESCC), yet epigenetic mechanisms underlying metastasis remain poorly defined. While DNMT1 and DNMT3A contribute to ESCC pathogenesis, DNMT3B's role is enigmatic despite frequent dysregulation. METHODS: Integrated methylome-transcriptome profiling comprised genome-wide methylation screening in 5 paired ESCC tumor and adjacent normal tissues. Parallel mRNA microarray profiling quantified expression levels of DNMT3B, CADM2, and ADAMTS9-AS2 in ESCC tumors. RIP, ChIP, and pyrosequencing in ESCC cells validated molecular interactions. RESULTS: ADAMTS9-AS2 downregulation promoted ESCC proliferation, migration, and invasion. Mechanistically, ADAMTS9-AS2 directly bound DNMT3B, preventing its occupancy at the CADM2. Rescue experiments confirmed CADM2 overexpression reversed ADAMTS9-AS2 knockdown-induced oncogenic phenotypes. Clinically, DNMT3B overexpression in lymph node-positive tumors correlated with metastatic progression. DISCUSSION: ADAMTS9-AS2 functions as an epigenetic brake by sequestering DNMT3B, thereby blocking CADM2 epigenetic silencing and metastasis in ESCC. Targeting this axis offers potential therapeutic strategies against ESCC.