ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicThe Role of RNA Regulation in Cancer Pathogenesis and Therapeutic StrategiesView all 4 articles
ADAMTS9-AS2 acts as an epigenetic brake to constrain DNMT3B-mediated CADM2 silencing in esophageal squamous cell carcinoma metastasis
Provisionally accepted
Fang-Fang Shen1*
Dong-Fen Li1Ling-Bei Kong1Jia-Le Li1Shi-Long Ma1Hao-Zhe Jiang1Hao-Zhe Yuan1Yan Jin2Zhi-Guo Chen2Xiu-Juan Guo1Gao-Pan Dong2De-Rong Lu1
Jiateng Zhong2- 1The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- 2Xinxiang Medical University, Xinxiang, China
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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.
Keywords: ADAMTS9-AS2, CADM2, DNMT3B, epigenetic therapy, esophageal squamous cell carcinoma, metastasis
Received: 24 Nov 2025; Accepted: 16 Feb 2026.
Copyright: © 2026 Shen, Li, Kong, Li, Ma, Jiang, Yuan, Jin, Chen, Guo, Dong, Lu and Zhong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Fang-Fang Shen
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