FTO-Mediated m6A Demethylation of SERPINF1 Attenuates Multiple Myeloma Progression via the Wnt/β-Catenin Pathway

Multiple myeloma (MM) is an intractable hematologic malignancy characterized by clonal growth of malignant plasma cells in the bone marrow. Recent studies have highlighted the role of N6-methyladenosine (m6A) RNA modifications in MM progression; however, the function of the m6A demethylase fat mass and obesity-associated protein (FTO) remains unclear. This study aims to explore the mechanisms by which FTO-mediated m6A demethylation of Serpin Family F Member 1 (SERPINF1) impacts MM progression. SERPINF1 and FTO expressions were assessed via real-time quantitative polymerase chain reaction (RT-qPCR). The impact of such expressions on MM was evaluated using CCK-8, EdU, transwell, and tumor xenograft model assays. Key molecules involved in the Wnt/β-catenin pathway were assessed via Western blotting. The relationship between SERPINF1 and FTO was determined through correlation analysis, methylated RNA immunoprecipitation, luciferase, RT-qPCR, Western blotting, RNA immunoprecipitation, and actinomycin D treatment assays. Finally, the effect of their interaction on MM was assessed through rescue experiments. SERPINF1 expression was reduced in MM samples. SERPINF1 overexpression suppressed the malignant traits of MM cells and reduced the levels of β-catenin, c-Myc, and cyclin D1. In vivo experiments revealed that SERPINF1 overexpression suppressed tumor growth in xenograft models. Mechanistically, FTO expression was upregulated in MM and SERPINF1 expression was negatively regulated by demethylating its m6A sites via IGF2BP1. Rescue experiments demonstrated that SERPINF1 overexpression reversed FTO-induced oncogenic phenotypes. These findings suggest that FTO-mediated m6A demethylation suppressed SERPINF1 expression in MM, whereas SERPINF1 overexpression inhibited tumor progression via the Wnt/β-catenin pathway.