YTHDF2-mediated m6A-dependent decay of DAB2 activates Wnt/β-catenin signaling to promote multiple myeloma proliferation

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by clonal expansion of malignant plasma cells. Although therapeutic advances have improved patient outcomes, relapse and disease progression remain frequent, highlighting the need to identify signaling mechanisms that sustain MM cell growth. Disabled homolog 2 (DAB2) is an adaptor protein involved in tumor suppression and signal transduction, but its biological role and upstream regulation in MM remain unclear. Public GEO datasets and clinical bone marrow specimens were analyzed to determine DAB2 expression and its prognostic significance in MM. Gain- and loss-of-function experiments were performed in MM cell lines to assess the effects of DAB2 on cell proliferation, apoptosis and cell cycle progression. RNA stability assays, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), dual-luciferase reporter assay, rescue experiments and xenograft models were used to define the regulatory mechanism linking YTHDF2, DAB2 and Wnt/β-catenin signaling. DAB2 expression was reduced in MM clinical specimens and selected public datasets, and lower expression was associated with high-risk disease features. Exploratory Kaplan–Meier analyses suggested survival associations in selected cohorts. Functionally, DAB2 knockdown enhanced MM cell proliferation, reduced apoptosis and promoted G1/S transition, whereas DAB2 overexpression suppressed MM cell proliferation, induced apoptosis and inhibited tumor growth in vivo. Mechanistically, DAB2 restrained Wnt/β-catenin signaling by limiting β-catenin nuclear translocation and reducing the expression of downstream proliferative targets, including c-Myc and Cyclin D1. Further investigation showed that the m6A reader YTHDF2 bound DAB2 mRNA and accelerated its degradation in an m6A-dependent manner. Silencing YTHDF2 increased DAB2 expression, impaired Wnt/β-catenin activation and suppressed MM cell proliferation, whereas DAB2 knockdown partially rescued the inhibitory effects induced by YTHDF2 depletion. Our findings identify DAB2 as a tumor suppressor in MM and reveal that YTHDF2-mediated m6A-dependent degradation of DAB2 activates Wnt/β-catenin signaling to promote MM proliferation. The YTHDF2/DAB2/Wnt/β-catenin axis may represent a potential therapeutic target for MM.