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

Multiple myeloma (MM) is a disorder of malignant plasma cells characterized by the clonal expansion of abnormal plasma cells within the bone marrow, which induces bone destruction, immunodeficiency, anemia, hypercalcemia, and renal dysfunction [1,2].It ranks second in prevalence among all hematological malignancies, accounting for nearly 10% of all blood cancers [3].Despite substantial advances in therapeutic strategies, particularly with the emergence of proteasome inhibitors, monoclonal antibodies, immunomodulatory drugs, and autologous stem cell transplantation, MM remains largely untreatable for a substantial proportion of patients owing to inevitable relapse and development of drug resistance [4].Hence, understanding the molecular pathogenesis of MM is critical for development of novel therapeutic targets and improving patient outcomes.Serpin Family F Member 1 (SERPINF1), also called PEDF, is a secreted glycoprotein and member of the serpin family that lacks protease inhibitory activity but displays various biological effects such as anti-angiogenic, anti-inflammatory, and antiproliferative functions [5,6].One study found that SERPINF1 expression was upregulated in during glioma cell tumorigenesis to enhance glioma progression and stemness [7].However, another study reported that metformin administration inhibited prostate cancer cell malignancy by upregulating the expression of SERPINF1, suggesting the inhibitory effects of SERPINF1 on prostate cancer progression [8].Consequently, SERPINF1 may 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/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 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/-catenin pathway.