MAGEC2 promotes tumorigenesis in multiple myeloma through USP16-mediated deubiquitination and stabilization of c-Myc.

Multiple myeloma (MM) is an incurable malignancy characterized by clonal plasma cell proliferation, in which dysregulated ubiquitination plays a key pathogenic role. Using bufalin as a molecular probe, we identified melanoma-associated antigen C2 (MAGEC2) as a direct binding target and investigated its unconventional function beyond canonical E3 ligase modulation. MAGEC2 expression and clinical relevance were analyzed in patient cohorts. Functional assays (MTT, Western blot, CCK-8, flow cytometry) and mechanistic studies (co-immunoprecipitation, mass spectrometry, ubiquitination assays) were performed in vitro and in an adoptive B-cell transfer mouse model. High MAGEC2 expression was significantly associated with poor overall survival in MM patients. Functionally, MAGEC2 promoted malignant proliferation and induced resistance to adriamycin and bortezomib. Mechanistically, in addition to its known role in enhancing E3 ligase activity, MAGEC2 directly bound and increased the deubiquitinase activity of USP16, leading to c-Myc stabilization via reduced ubiquitination. Interactions among MAGEC2, USP16, and c-Myc were confirmed both in vitro and in vivo, establishing a MAGEC2-USP16-c-Myc axis. MAGEC2 overexpression also exacerbated bone lesions in vivo. Collectively, these findings identify MAGEC2 as both a prognostic biomarker and a promising therapeutic target in MM, and highlight its role as a multifunctional regulator of the ubiquitin system.