NSUN2 Negatively Regulates TP53 mRNA Stability to Promote the Malignant Progression of Nasopharyngeal Carcinoma

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.