N6-methyladenosine (mA) is the most common and abundant mRNA modification, playing an essential role in biological processes and tumor development. However, the role of mA methylation in skin cutaneous melanoma (SKCM) is not yet clear. This study analyzed the expression of mA-related functional genes in SKCM and aimed to explore the key demethylase ALKBH5 mediated mA modification and its potential mechanism in human SKCM.Based on public databases, the mA-related gene expression landscape in SKCM was portrayed. MeRIP-Seq and RNA-Seq were used to recognize the downstream target of ALKBH5.andfunctional phenotype and rescue functional experiments were performed to explore the mechanism of the ALKBH5-mA-ABCA1 axis in SKCM.We found ALKBH5 upregulated in SKCM, associated with poor prognosis. ALKBH5 can promote melanoma cell proliferation, colony formation, migration, and invasion and inhibit autophagy, facilitating tumor growth and metastasis. We identified ABCA1, a membrane protein that assists cholesterol efflux, as a downstream target of ALKBH5-mediated mA demethylation. Finally, our data demonstrated that ALKBH5 promoted SKCM via mediating ABCA1 downregulation by reducing ABCA1 mRNA stability in an mA-dependent manner.Our findings exhibited the functional value of the key demethylase ALKBH5 mediated mA modification in the progression of SKCM, suggesting the ALKBH5-mA-ABCA1 axis as a potential therapeutic target in SKCM. Background: Methods: Results: Conclusion: 6 6 6 6 6 6 6 6 6 6In vivo in vitro in vitro in vivo
