WTAP Suppresses Cutaneous Melanoma Progression by Upregulation of KLF9: Insights into m6A-Mediated Epitranscriptomic Regulation.

Background: N6-methyladenosine (m6A) modification plays a crucial role in tumor biology; however, the function of the methyltransferase adaptor WTAP in melanoma remains poorly understood. Methods: We analyzed WTAP expression and its clinical relevance using TCGA-SKCM and GTEx datasets, followed by immunohistochemical validation in melanoma tissues. The biological effects of WTAP were assessed through gain- and loss-of-function experiments in melanoma cell lines. Weighted gene co-expression network analysis (WGCNA) and LASSO regression were used to identify key WTAP-related genes. Results: WTAP expression was significantly decreased in melanoma compared with normal skin and was negatively correlated with tumor progression and poor survival. Functionally, WTAP overexpression suppressed melanoma cell proliferation and migration, whereas its knockdown produced the opposite effects. Bioinformatic analyses and rescue experiments identified KLF9 as a potential downstream effector of WTAP. WTAP depletion reduced KLF9 mRNA and protein levels, while overexpression restored them. Moreover, MeRIP-qPCR confirmed that WTAP promotes m6A enrichment on KLF9 mRNA, suggesting a post-transcriptional regulatory mechanism. Conclusions: Our findings reveal a novel WTAP-KLF9 axis that mediates melanoma suppression through m6A-dependent regulation. This study provides new insight into the context-specific role of WTAP in melanoma and suggests it may serve as a potential biomarker or therapeutic target.