Background: Among head and neck squamous cell carcinomas (HNSCCs), hypopharyngeal squamous cell carcinoma (HPSCC) has the worst prognosis. Iron metabolism, which plays a crucial role in tumor progression, is mainly regulated by alterations to genes and post-transcriptional processes. The recent discovery of the N6-methyladenosine (m⁶A) modification has expanded the realm of previously undiscovered post-transcriptional gene regulation mechanisms in eukaryotes. Many studies have demonstrated that m⁶A methylation represents a distinct layer of epigenetic deregulation in carcinogenesis and tumor proliferation. However, the status of m⁶A modification and iron metabolism in HPSCC remains unknown./nMethods: Bioinformatics analysis, sample analysis, and transcriptome sequencing were performed to evaluate the correlation between m⁶A modification and iron metabolism. Iron metabolic and cell biological analyses were conducted to evaluate the effect of the m⁶A reader YTHDF1 on HPSCC proliferation and iron metabolism. Transcriptome-wide m⁶A-seq and RIP-seq data were mapped to explore the molecular mechanism of YTHDF1 function in HPSCC./nResults: YTHDF1 was found to be closely associated with ferritin levels and intratumoral iron concentrations in HPSCC patients at Sir Run Run Shaw Hospital. YTHDF1 induced-HPSCC tumorigenesis depends on iron metabolism in vivo in vitro. Mechanistically, YTHDF1 methyltransferase domain interacts with the 3'UTR and 5'UTR of TRFC mRNA, then further positively regulates translation of m⁶A-modified TFRC mRNA. Gain-of-function and loss-of-function analyses validated the finding showing that TFRC is a crucial target gene for YTHDF1-mediated increases in iron metabolism./nConclusion: YTHDF1 enhanced TFRC expression in HPSCC through an m⁶A-dependent mechanism. From a therapeutic perspective, targeting YTHDF1 and TFRC-mediated iron metabolism may be a promising strategy for HPSCC.

中文翻译：

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YTHDF1 增强的铁代谢取决于 TFRC m6A 甲基化

背景：在头颈部鳞状细胞癌 (HNSCC) 中，下咽鳞状细胞癌 (HPSCC) 的预后最差。铁代谢在肿瘤进展中起关键作用，主要受基因改变和转录后过程的调节。最近发现的 N6-甲基腺苷 (m ⁶ A) 修饰扩展了真核生物中先前未发现的转录后基因调控机制的领域。许多研究表明，m ⁶ A 甲基化代表了致癌作用和肿瘤增殖中表观遗传失调的独特层。然而，HPSCC中 m ⁶ A 修饰和铁代谢的状态仍然未知。/n方法：进行生物信息学分析、样品分析和转录组测序以评估 m ⁶ A 修饰与铁代谢之间的相关性。进行铁代谢和细胞生物学分析以评估 m ⁶ A 阅读器 YTHDF1 对 HPSCC 增殖和铁代谢的影响。转录组范围内的 m ⁶ A-seq 和 RIP-seq 数据被映射以探索 YTHDF1 在 HPSCC 中功能的分子机制。/n结果：在 Sir Run 发现 YTHDF1 与 HPSCC 患者的铁蛋白水平和瘤内铁浓度密切相关逸夫医院。YTHDF1 诱导的 HPSCC 肿瘤发生依赖于体内 体外铁代谢. 从机制上讲，YTHDF1 甲基转移酶结构域与 TRFC mRNA 的 3'UTR 和 5'UTR 相互作用，然后进一步正向调节 m ⁶ A 修饰的 TFRC mRNA 的翻译。功能获得和功能丧失分析证实了这一发现，表明 TFRC 是 YTHDF1 介导的铁代谢增加的关键靶基因。/n结论： YTHDF1 通过 m ⁶ A 依赖性机制增强 HPSCC 中的 TFRC 表达. 从治疗的角度来看，靶向 YTHDF1 和 TFRC 介导的铁代谢可能是 HPSCC 的一种有前景的策略。