UBE2M inhibits neoplastic cell proliferation via MKK7-JNK-EGR1 axis in melanoma.

BACKGROUND: Dysregulated neddylation is often associated with tumorigenesis and malignant progression in multiple kinds of cancers. However, tumor-specific neddylation substrates exist across cancer types, leading to distinct pathological and therapeutic implications. Therefore, precisely targeting tumor-specific neddylation substrates is of critical importance for achieving precision therapy in cancer treatment. METHODS: The expression of UBE2M was examined in human melanoma tissues using western blotting and immunofluorescence (IF). Functional assays evaluated its effects on melanoma cell proliferation in vitro and in vivo, as well as on cell migration in vitro. Mechanistic investigations integrated transcriptomic analysis, real-time quantitative PCR (RT-qPCR), Kaplan-Meier survival analysis, co-immunoprecipitation (Co-IP) assays, cycloheximide (CHX) chase assays, and proximity ligation assays (PLA) to elucidate signaling pathways and molecular mechanisms underlying the role of UBE2M in melanoma. RESULTS: UBE2M, the predominant E2 enzyme in the neddylation pathway, was markedly downregulated in human melanoma tissues, implicating impaired neddylation in melanoma pathogenesis. Mechanistically, we identified mitogen-activated protein kinase kinase 7 (MKK7) as a direct neddylation substrate of UBE2M. Neddylation of MKK7 inhibits its ubiquitination and proteasomal degradation, thereby stabilizing MKK7 and enhancing its phosphorylation. Activation of MKK7 consequently triggers JNK signaling, induces early growth response factor 1 (EGR1), and suppresses CCND2 expression, collectively restraining melanoma cell proliferation. CONCLUSIONS: This study establishes UBE2M as a critical tumor suppressor in melanoma through the MKK7 neddylation-JNK-EGR1 axis and highlights its potential as a therapeutic target.