ADAMTS9-AS2 acts as an epigenetic brake to constrain DNMT3B-mediated CADM2 silencing in esophageal squamous cell carcinoma metastasis

TL;DR

This study reveals how the lncRNA ADAMTS9-AS2 prevents ESCC metastasis by blocking DNMT3B from silencing the CADM2 gene through epigenetic mechanisms.

Contribution

Identifies ADAMTS9-AS2 as a novel epigenetic regulator that constrains DNMT3B-mediated CADM2 silencing in ESCC metastasis.

Findings

ADAMTS9-AS2 downregulation promotes ESCC proliferation, migration, and invasion.

ADAMTS9-AS2 binds DNMT3B, preventing its occupancy at CADM2 and subsequent gene silencing.

DNMT3B overexpression in lymph node-positive tumors correlates with metastatic progression in ESCC.

Abstract

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.

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.

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.

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.

In the physiological condition (left panel), the lncRNA ADAMTS9-AS2 sequesters DNMT3B, preventing its binding to the CADM2 gene and thereby maintaining a transcriptionally permissive, hypomethylated state. In the ESCC pathological condition (right panel), the downregulation of ADAMTS9-AS2 releases DNMT3B, which subsequently binds to CADM2, leading to CpG hypermethylation and epigenetic silencing of the gene. This DNMT3B-mediated silencing of CADM2 ultimately​ drives ESCC metastasis.Infographic illustrates physiological and pathological states of CADM2 regulation. Left shows ADAMTS9-AS2 sequestering DNMT3B away from CADM2 in the physiological state, preserving unmethylated DNA. Right depicts ADAMTS9-AS2 downregulation, DNMT3B binding to CADM2, causing methylation, gene silencing, and loss of CADM2 expression.

In the physiological condition (left panel), the lncRNA ADAMTS9-AS2 sequesters DNMT3B, preventing its binding to the CADM2 gene and thereby maintaining a transcriptionally permissive, hypomethylated state. In the ESCC pathological condition (right panel), the downregulation of ADAMTS9-AS2 releases DNMT3B, which subsequently binds to CADM2, leading to CpG hypermethylation and epigenetic silencing of the gene. This DNMT3B-mediated silencing of CADM2 ultimately​ drives ESCC metastasis.

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