RNA methyltransferase NSUN5 promotes oral squamous cell carcinoma proliferation and migration by enhancing YAP1 expression in an m5C-dependent manner.

m5C modifications play a critical role in the development of oral squamous cell carcinoma (OSCC). NSUN5 is a key methyltransferase that catalyzes m5C modification of mammalian mRNAs. However, its role in OSCC regulation remains unclear. This study aimed to explore the potential oncogenic activity and molecular mechanisms of NSUN5 in OSCC progression. A total of 34 tumor and adjacent normal tissue samples were collected from patients with OSCC prior to chemotherapy. Seven OSCC cell lines (HN6, SCC-25, CAL-27, SCC-9, SCC-15, SCC-4, and HSC3) were used. qRT-PCR, western blotting, and immunohistochemistry analyses were conducted to assess NSUN5 expression in OSCC tumors. The influence of NSUN5 on cell proliferation, migration, and invasion was evaluated using CCK8, colony formation, and wound healing assays. The downstream signaling pathways of NSUN5 in OSCC were identified. The YAP1 expression level was detected, and m5C modification in NSUN5-silenced and control OSCC cells was measured. NSUN5 was found to be upregulated in OSCC tumor tissues and associated with poor patient prognosis. It promotes OSCC cell proliferation, colony formation, and migration in vitro, as well as tumor growth in vivo. Mechanistically, NSUN5 catalyzes m5C modification of YAP1 mRNA, stabilizing it and increasing its expression. The role of NSUN5 in OSCC progression is dependent on YAP1 mRNA expression levels. This study reveals a novel function of NSUN5 in regulating YAP1 expression and identifies a previously unknown NSUN5/YAP1 pathway in OSCC cells.