COMMD4 Drives Skin Cutaneous Melanoma Progression by Targeting PI3K‐p85 to Activate PI3K‐AKT

Skin cutaneous melanoma (SKCM), the most aggressive form of cutaneous malignancy globally, remains poorly understood in terms of its molecular drivers. Although the copper metabolism MURR1 domain (COMMD) protein family has been associated with oncogenesis, its functional relevance in SKCM is undefined. In this study, we identified COMMD4 as a prognostic biomarker of SKCM and showed that it is positively correlated with the adverse clinical outcomes of patients. COMMD4 gene knockout (COMMD4‐KO) impaired the proliferative, migratory, and invasive capacities of SKCM cells in vitro and suppressed xenograft tumor growth in vivo. Mechanistically, COMMD4‐KO induced G2/M phase arrest by disrupting p21‐CDK1‐cyclinB1 and impeded epithelial‐mesenchymal transition (EMT) by reversing the E/N cadherin switch. We also demonstrate that COMMD4 activates PI3K‐AKT signaling by binding PI3K‐p85 to release PI3K‐p110, thereby driving G2/M transition and EMT. Reactivation of PI3K‐AKT signaling in COMMD4‐KO cells rescued oncogenic phenotypes. By integrative Connectivity Map analysis and functional validation, we identified triamterene as a pharmacological inhibitor targeting the COMMD4‐PI3K‐AKT axis, which suppressed the progression of SKCM effectively in vitro and vivo. Our findings establish the COMMD4‐PI3K‐AKT axis as a novel and critical regulator of SKCM progression and repurpose triamterene as a promising therapeutic agent against SKCM.