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Background <p>Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor. N4-acetylcytidine (ac4C) modification regulates mRNA stability and contributes to tumorigenesis. FOXD1, a crucial transcription factor, acts as a tumor-promoting factor in NPC. However, its molecular underpinnings are not fully elucidated.</p> Methods <p>Expression of mRNA and protein was quantified by quantitative PCR, immunohistochemistry, or immunoblotting. The effects on cell phenotypes were determined by assessing NPC cell proliferation, apoptosis, invasiveness, sphere formation, and TUVEC tube formation. The interaction between FOXD1 and N-acetyltransferase 10 (NAT10) was predicted by online computational methods and validated using RIP, mRNA stability, ChIP, and luciferase assays. Xenograft studies were performed to observe the in vivo effects.</p> Results <p>FOXD1 expression was increased in NPC clinical samples and cell lines. Functionally, FOXD1 depletion suppressed NPC cell growth, invasion, sphere formation ability, while promoting cell apoptosis and impairing HUVEC tube formation. Mechanistically, NAT10 stabilized FOXD1 mRNA by mediating its ac4C modification. FOXD1 upregulation counteracted NAT10 depletion-driven cellular phenotypic alterations. In turn, FOXD1 acted as a transcriptional activator of NAT10 in NPC cells. NAT10 reconstitution reversed FOXD1 depletion-driven cellular phenotypic alterations. Additionally, NAT10 knockdown inhibited NPC xenograft growth in vivo by reducing FOXD1 levels.</p> Conclusion <p>Our study demonstrates that a mutually reinforcing FOXD1/NAT10 positive feedback loop drives NPC progression, providing new therapeutic vulnerabilities for clinical intervention.</p>

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The FOXD1/NAT10 positive feedback loop drives nasopharyngeal carcinoma progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Leifeng Liu,
  • Qizhu Chen,
  • Yiling Li,
  • Weihao Wu,
  • Feng Jiang,
  • Haitao Qiu

摘要

Background

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor. N4-acetylcytidine (ac4C) modification regulates mRNA stability and contributes to tumorigenesis. FOXD1, a crucial transcription factor, acts as a tumor-promoting factor in NPC. However, its molecular underpinnings are not fully elucidated.

Methods

Expression of mRNA and protein was quantified by quantitative PCR, immunohistochemistry, or immunoblotting. The effects on cell phenotypes were determined by assessing NPC cell proliferation, apoptosis, invasiveness, sphere formation, and TUVEC tube formation. The interaction between FOXD1 and N-acetyltransferase 10 (NAT10) was predicted by online computational methods and validated using RIP, mRNA stability, ChIP, and luciferase assays. Xenograft studies were performed to observe the in vivo effects.

Results

FOXD1 expression was increased in NPC clinical samples and cell lines. Functionally, FOXD1 depletion suppressed NPC cell growth, invasion, sphere formation ability, while promoting cell apoptosis and impairing HUVEC tube formation. Mechanistically, NAT10 stabilized FOXD1 mRNA by mediating its ac4C modification. FOXD1 upregulation counteracted NAT10 depletion-driven cellular phenotypic alterations. In turn, FOXD1 acted as a transcriptional activator of NAT10 in NPC cells. NAT10 reconstitution reversed FOXD1 depletion-driven cellular phenotypic alterations. Additionally, NAT10 knockdown inhibited NPC xenograft growth in vivo by reducing FOXD1 levels.

Conclusion

Our study demonstrates that a mutually reinforcing FOXD1/NAT10 positive feedback loop drives NPC progression, providing new therapeutic vulnerabilities for clinical intervention.