WTAP-mediated m6A methylation of SOX2 affects lung adenocarcinoma malignancy via Wnt/β-catenin pathway

Lung adenocarcinoma (LUAD) is one of the most common subtypes of lung cancer, characterized by high incidence and mortality rates. SOX2 is a transcription factor associated with the progression of various cancers. The role of the SOX2-Wnt/β-catenin signaling axis in LUAD has been previously reported; however, the upstream epitranscriptomic regulatory mechanisms governing SOX2, particularly the effects of m6A methylation on its expression, remain poorly elucidated. This study aims to investigate the role of SOX2 in the malignant progression of LUAD and its regulatory mechanisms, particularly its relationship with Wilms' tumor 1-associating protein (WTAP).

Bioinformatics analysis was used to analyze LUAD transcriptome data in the TCGA database, and to analyze the differential expression of SOX2 and WTAP. LUAD patient samples were collected for validation. The A549 cell line was used to construct SOX2 knockdown and WTAP overexpression models. The cell phenotype changes, signaling pathway protein expression, m6A methylation levels, and mRNA stability were evaluated using qRT-PCR, Western blotting, colony formation assay, Transwell assay, flow cytometry, m6A Dot blot assay, and RNA stability assay. Data analysis was conducted using SPSS software, with a significance level set at P < 0.05.

SOX2 was highly expressed in LUAD tissues, while WTAP expression was downregulated. Knockdown of SOX2 significantly inhibited the proliferation, migration, and invasion of LUAD cells and enhanced cell apoptosis (P < 0.05). WTAP reduced the stability of SOX2 mRNA through m6A modification, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway and suppressing the malignant progression of LUAD (P < 0.05).

This study reveals the oncogenic role of SOX2 in LUAD and its regulatory mechanism through the Wnt/β-catenin signaling pathway. It also elucidates the crucial role of WTAP in regulating SOX2 stability via m6A modification. These findings provide new potential therapeutic targets for LUAD, but further validation in animal models is needed.