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<p>Esophageal squamous cell carcinoma (ESCC) remains a lethal malignancy with a poor 5-year survival rate of approximately 20%, necessitating the identification of novel therapeutic targets. Here, we show that KDM4A is significantly upregulated in esophageal squamous cell carcinoma (ESCC) and its high expression correlates with poor prognosis. Functional assays demonstrated that KDM4A promotes ESCC cell proliferation, migration, invasion, and tumor growth in vitro and in vivo. Mechanistically, KDM4A demethylates H3K9me3 at the LRG1 promoter, thereby enhancing LRG1 transcription and activating the TGF-β pathway to drive epithelial-mesenchymal transition (EMT) and cancer stemness. Knockdown of KDM4A or LRG1 suppresses these oncogenic phenotypes, while LRG1 overexpression rescues KDM4A deficiency–induced impairments. Clinically, KDM4A and LRG1 are co-overexpressed in ESCC tissues and associated with advanced tumor stage and shorter overall survival. These findings identify the KDM4A–LRG1–TGF-β axis as a critical driver of ESCC progression and a potential therapeutic target.</p>

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The histone demethylase KDM4A promotes esophageal cancer progression by epigenetically activating LRG1-mediated TGF-β signaling

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Yueting Han,
  • Huiya Wang,
  • Yaoyang Guo,
  • Hongdian Zhang,
  • Xinyi Wen,
  • Miao Zhang,
  • Zhanhua Gao,
  • Jie Hao,
  • Minghan Qiu,
  • Li Ren,
  • Dongzhi Hu,
  • Yi Ba,
  • Bei Sun,
  • Haiyang Zhang

摘要

Esophageal squamous cell carcinoma (ESCC) remains a lethal malignancy with a poor 5-year survival rate of approximately 20%, necessitating the identification of novel therapeutic targets. Here, we show that KDM4A is significantly upregulated in esophageal squamous cell carcinoma (ESCC) and its high expression correlates with poor prognosis. Functional assays demonstrated that KDM4A promotes ESCC cell proliferation, migration, invasion, and tumor growth in vitro and in vivo. Mechanistically, KDM4A demethylates H3K9me3 at the LRG1 promoter, thereby enhancing LRG1 transcription and activating the TGF-β pathway to drive epithelial-mesenchymal transition (EMT) and cancer stemness. Knockdown of KDM4A or LRG1 suppresses these oncogenic phenotypes, while LRG1 overexpression rescues KDM4A deficiency–induced impairments. Clinically, KDM4A and LRG1 are co-overexpressed in ESCC tissues and associated with advanced tumor stage and shorter overall survival. These findings identify the KDM4A–LRG1–TGF-β axis as a critical driver of ESCC progression and a potential therapeutic target.