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<p><i>Helicobacter pylori (H. pylori)</i> cytotoxin-associated gene A (CagA) critically contributes to gastric cancer (GC) pathogenesis, though its epigenetic control of cancer stemness is incompletely characterized. This study establishes that CagA enhances self-renewal capacity and metastatic potential in GC cells by elevating DNA methyltransferase 1 (DNMT1) expression. Upregulated DNMT1 catalyzes hypermethylation of the brain-expressed X-linked gene 1 (BEX1) promoter, resulting in transcriptional silencing of this tumor suppressor. Functional validation through tumorsphere/colony formation assays and transcriptomic profiling confirmed DNMT1-mediated BEX1 suppression as essential for sustaining stemness phenotypes. Crucially, in vivo models demonstrated that BEX1 overexpression reverses CagA-driven tumor growth and pulmonary metastasis, while BEX1 knockdown compromises the anti-tumor efficacy of DNA methyltransferase inhibitor 5-aza-2’-deoxycytidine (DAC). These findings define a novel pathogenic cascade wherein CagA initiates DNMT1-dependent epigenetic silencing of BEX1 to maintain cancer stemness. The mechanistic identification of this CagA-DNMT1-BEX1 axis provides a therapeutic rationale for targeting DNMT1 activity and restoring BEX1 function in metastatic GC.</p><p></p>

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CagA promotes gastric cancer stemness and metastasis via DNMT1-mediated epigenetic silencing of BEX1

  • 期刊论文

  • 发表日期：

    2026年7月16日

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  • Yan Wang,
  • Dajun Chen,
  • Shuai Qian,
  • Fengping Wang,
  • Huibin Weng

摘要

Helicobacter pylori (H. pylori) cytotoxin-associated gene A (CagA) critically contributes to gastric cancer (GC) pathogenesis, though its epigenetic control of cancer stemness is incompletely characterized. This study establishes that CagA enhances self-renewal capacity and metastatic potential in GC cells by elevating DNA methyltransferase 1 (DNMT1) expression. Upregulated DNMT1 catalyzes hypermethylation of the brain-expressed X-linked gene 1 (BEX1) promoter, resulting in transcriptional silencing of this tumor suppressor. Functional validation through tumorsphere/colony formation assays and transcriptomic profiling confirmed DNMT1-mediated BEX1 suppression as essential for sustaining stemness phenotypes. Crucially, in vivo models demonstrated that BEX1 overexpression reverses CagA-driven tumor growth and pulmonary metastasis, while BEX1 knockdown compromises the anti-tumor efficacy of DNA methyltransferase inhibitor 5-aza-2’-deoxycytidine (DAC). These findings define a novel pathogenic cascade wherein CagA initiates DNMT1-dependent epigenetic silencing of BEX1 to maintain cancer stemness. The mechanistic identification of this CagA-DNMT1-BEX1 axis provides a therapeutic rationale for targeting DNMT1 activity and restoring BEX1 function in metastatic GC.