Background:Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in China, often diagnosed at advanced stages. The 5-methylcytosine (m5C) RNA modification plays a crucial role in tumorigenesis, influencing cell proliferation, differentiation, metabolism, invasion, metastasis, and immune evasion. NSUN2, a key m5C methyltransferase, has been implicated in various cancers, but its role in NPC remains unclear.Methods:NSUN2 expression in NPC tissues was explored by bioinformatics analysis, qPCR, Western blot, and immunohistochemistry. Functional roles of NSUN2 in proliferation, apoptosis, migration, and invasion were evaluated in NPC cell lines using CCK-8, colony formation, flow cytometry, wound-healing and transwell assays. The mechanism by which NSUN2 regulates TP53 was investigated by m5C-RIP, RNA stability assays, dual-luciferase reporter assay and rescue experiments. The NSUN2/TP53 axis was further validated in vivo through xenograft mouse models.Results:NSUN2 is significantly overexpressed in NPC tissues, and its high expression correlates with poor prognosis. Functional assays reveal that NSUN2 promotes NPC cell proliferation, migration, and invasion and inhibits apoptosis. Mechanistically, NSUN2 negatively regulates TP53 expression by increasing m5C modification at the CDS 1228 site, thereby decreasing TP53 mRNA stability and expression. Knockdown of TP53 counteracts the inhibitory effects of NSUN2 knockdown on proliferation, migration, and invasion in NPC cells. Additionally, in vivo experiments revealed that NSUN2 knockdown suppresses tumor growth in xenograft models, while TP53 knockdown reverses the growth-inhibitory effect of NSUN2 knockdown on xenograft tumors.Conclusions:Our findings indicate that NSUN2 partially negatively regulates TP53 mRNA stability, promoting malignant progression and acting as an oncogene in NPC by downregulating TP53 through m5C modification. Thus, targeting the NSUN2/TP53 axis could be a potential therapeutic strategy for NPC.
背景：鼻咽癌是中国高发的恶性肿瘤，常于晚期确诊。5-甲基胞嘧啶（m5C）RNA修饰在肿瘤发生中起关键作用，影响细胞增殖、分化、代谢、侵袭、转移及免疫逃逸。NSUN2作为重要的m5C甲基转移酶，已在多种癌症中被证实具有重要作用，但其在鼻咽癌中的功能尚不明确。 方法：通过生物信息学分析、qPCR、Western blot及免疫组化检测NSUN2在鼻咽癌组织中的表达水平。采用CCK-8、克隆形成、流式细胞术、划痕愈合及Transwell实验评估NSUN2对鼻咽癌细胞增殖、凋亡、迁移和侵袭的功能影响。通过m5C-RIP、RNA稳定性检测、双荧光素酶报告基因及挽救实验探究NSUN2调控TP53的作用机制。利用异种移植小鼠模型在体内验证NSUN2/TP53轴的功能。 结果：NSUN2在鼻咽癌组织中显著高表达，且其高表达与不良预后相关。功能实验表明NSUN2促进鼻咽癌细胞增殖、迁移和侵袭，并抑制细胞凋亡。机制研究发现，NSUN2通过在CDS 1228位点增加m5C修饰，降低TP53 mRNA稳定性及表达水平，从而负向调控TP53。敲低TP53可逆转NSUN2敲低对鼻咽癌细胞增殖、迁移和侵袭的抑制作用。体内实验进一步证实，NSUN2敲低可抑制异种移植瘤生长，而TP53敲低则能逆转NSUN2敲低对移植瘤生长的抑制作用。 结论：本研究揭示NSUN2通过m5C修饰下调TP53表达，部分负向调控TP53 mRNA稳定性，从而促进鼻咽癌恶性进展，发挥癌基因功能。靶向NSUN2/TP53轴可能成为鼻咽癌的潜在治疗策略。
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