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<p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) RNA modification is a pivotal post-transcriptional regulator of RNA metabolism and cancer progression. Fat mass and obesity-associated protein (FTO), an m<sup>6</sup>A demethylase, has emerged as a potent oncogenic driver across multiple malignancies. In this study, we demonstrate that FTO directly demethylates the primary transcripts of the miR-200b/a/429 cluster, thereby impeding DGCR8-mediated recognition and processing. The ensuing reduction in mature tumor-suppressive miR-200b/a/429 relieves repression of a suite of downstream targets intimately linked to metastasis and cell proliferation, ultimately accelerating tumor growth and lymph-node dissemination in esophageal squamous cell carcinoma (ESCC). Pharmacologic inhibition of FTO restores miR-200b/a/429 cluster expression and partially rescues the oncogenic phenotype elicited by FTO overexpression. Collectively, our findings uncover a previously unrecognized FTO-m<sup>6</sup>A-miR-200b/a/429 axis that propels ESCC progression and highlight FTO as a promising therapeutic target for patients with ESCC.</p>

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Targeting FTO shows therapeutic potential in esophageal squamous cell carcinoma by modulating microRNA biogenesis

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Wei Zhou,
  • Chunyan Wang,
  • Changhao Li,
  • Pengxiang Chen,
  • Yuchen Liu,
  • Hongyuan Mao,
  • Pengfei Zhu,
  • Yuxiao Gong,
  • Yufeng Cheng,
  • Lin Zhang

摘要

N6-methyladenosine (m6A) RNA modification is a pivotal post-transcriptional regulator of RNA metabolism and cancer progression. Fat mass and obesity-associated protein (FTO), an m6A demethylase, has emerged as a potent oncogenic driver across multiple malignancies. In this study, we demonstrate that FTO directly demethylates the primary transcripts of the miR-200b/a/429 cluster, thereby impeding DGCR8-mediated recognition and processing. The ensuing reduction in mature tumor-suppressive miR-200b/a/429 relieves repression of a suite of downstream targets intimately linked to metastasis and cell proliferation, ultimately accelerating tumor growth and lymph-node dissemination in esophageal squamous cell carcinoma (ESCC). Pharmacologic inhibition of FTO restores miR-200b/a/429 cluster expression and partially rescues the oncogenic phenotype elicited by FTO overexpression. Collectively, our findings uncover a previously unrecognized FTO-m6A-miR-200b/a/429 axis that propels ESCC progression and highlight FTO as a promising therapeutic target for patients with ESCC.