YTHDF2 enhances proliferation and metastasis of nasopharyngeal carcinoma by mediating m6A modification in destabilizing FOXO1 mRNA.

Abstract

Background: Aberrant N6-methyladenosine (m6A) modification is linked to cancer development and progression. However, the role of YTH N6-methyladenosine RNA binding protein F2 (YTHDF2), an m6A 'reader protein', in nasopharyngeal carcinoma (NPC) is poorly understood. This study aimed to clarify the role and mechanism of YTHDF2 in NPC development.

Methods: Bioinformatics analysis was performed to identify the differential expression, prognostic value, and enriched pathways of YTHDF2 in patients with NPC. Quantitative PCR, western blotting, and immunohistochemistry were used to detect mRNA and protein expression. Biological function of YTHDF2 was investigated using in vitro experiments, including proliferation, wound healing, and invasion assays. RNA immunoprecipitation sequencing (RIP-seq), RIP-qPCR, and Methylated RNA immunoprecipitation sequencing (MeRIP-seq) were employed to determine if YTHDF2 modulates forkhead box O1 (FOXO1) expression through m6A modification.

Results: YTHDF2 mRNA and protein levels were significantly increased in the NPC tissues and cell lines. Higher expression of YTHDF2 was associated with a poorer prognosis. Overexpressing YTHDF2 enhanced the NPC cell proliferation, migration, and invasion. Conversely, YTHDF2 knockdown inhibited these phenomena. Gene set enrichment analysis revealed that FOXO1-related signaling pathways were enriched in the YTHDF2-activated group. Mechanistically, YTHDF2 overexpression inhibited FOXO1 expression in NPC cells. RIP-seq, RIP-qPCR, and MeRIP-seq assays confirmed that YTHDF2 was bound to FOXO1 mRNA, reducing its stability and accelerated degradation.

Conclusion: YTHDF2 potentially functions as an oncogene in NPC by binding to the m6A site of FOXO1, reducing its expression, thereby promoting malignant behavior. It may also be a viable biomarker and therapeutic target for NPC.