The FOXD1/NAT10 positive feedback loop drives nasopharyngeal carcinoma progression.

Abstract

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.