COMMD4, a novel driver for skin cutaneous melanoma progression via targeting p85 to activate PI3K/Akt signaling

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. Overall design: In this study, we identified COMMD4 as a prognostic biomarker upregulated in SKCM tissues and correlated with adverse clinical outcomes. COMMD4 knockout (COMMD4-KO) impaired proliferative, migratory, and invasive capacities of SKCM cells in vitro and suppressed xenograft tumor growth in vivo. Mechanistically, COMMD4 deficiency induced G2/M phase arrest by disrupting the p21-CDK1/cyclin B1 axis and impeded epithelial-mesenchymal transition (EMT). We further demonstrated that COMMD4 directly interacts with the p85 regulatory subunit to activate PI3K/Akt signaling to drive G2/M transition and EMT. Reconstitution of PI3K/Akt signaling in COMMD4-KO cells rescued these oncogenic phenotypes. Through integrative Connectivity Map analysis and functional validation, we identified triamterene as a pharmacological inhibitor targeting the COMMD4-PI3K/Akt axis, which effectively suppressed SKCM progression in vitro and vivo. Our findings establish the COMMD4-PI3K/Akt axis as a critical regulator of SKCM progression and propose triamterene repurposing as a promising therapeutic strategy against SKCM