RNA Methyltransferase NSUN5 Promotes Esophageal Cancer via 5‐Methylcytosine Modification of METTL1

Aberrant RNA modifications can drive carcinogenic transformation and tumor progression, with 5-methylcytosine (m5C) emerging as one of the predominant RNA modifications in eukaryotic cells. However, the function and molecular mechanisms of m5C in esophageal cancer (ESCA) remain insufficiently defined. Here we report that the m5C methyltransferase NOP2/Sun domain family member 5 (NSUN5) is significantly upregulated in ESCA tumors and shows promising diagnostic potential. Functionally, knockdown of NSUN5 impairs the proliferation capacity of ESCA cells and arrests cell cycle at the G0/G1 phase, while enforced expression of NSUN5 accelerates ESCA progression. In vivo, deficiency of NSUN5 significantly reduces tumor growth in a cell-based xenograft mouse model. Mechanistically, NSUN5 correlates with the oncogenic methyltransferase like 1 (METTL1), positively regulating its expression; NSUN5 binds directly to the METTL1 transcript, facilitating its m5C modification in ESCA cells. Additionally, overexpression of METTL1 effectively counteracts the tumor-suppressive effects resulting from NSUN5 ablation in both in vitro and in vivo settings. A comprehensive pan-cancer analysis further underscores NSUN5's essential role in digestive system tumors, with downregulation of NSUN5 notably inhibiting gastric and colon cancer cell growth. These findings provide new insights into epigenetic regulation in ESCA and propose the NSUN5/METTL1 axis as a promising therapeutic target for this malignancy.