Abstract
The E3 ligase TRIM63 demonstrates a robust correlation with melanoma malignancy, particularly in cases involving BRAF mutants. Meanwhile, BRAF mutants, such as V600E, represent a prominent mutation observed in melanoma patients, yet the underlying mechanism remains elusive. In this study, we demonstrate that TRIM63 exhibits overexpression in melanoma cells and exerts its full oncogenic potential upon activation of the MAPK signaling pathway. Mechanistically, BRAF mutation induces ERK1/2-mediated phosphorylation of TRIM63 at serine 69 (S69). TRIM63 S69 is localized in the RING domain, and its phosphorylation enhances TRIM63 binding with IRF-8. Subsequently, TRIM63 leads to the ubiquitination of IRF-8 at lysine 250 (K250). The degradation of IRF-8 ultimately contributes to tumor progression enhancement. Clinically, the presence of pS69 on TRIM63 is associated with tumor immunosuppression and poor prognosis among melanoma patients, highlighting its potential as a promising therapeutic target.