USP10 stabilizes FOXM1 through KAT5-mediated acetylation to suppress cell senescence and promote melanoma malignant progression.

The ubiquitin signaling cascade plays a pivotal role in multiple cancer types, yet its role in melanoma progression remains incompletely elucidated. An unbiased and systematic analysis indicates that Ubiquitin-specific peptidase 10 (USP10), a member of USP gene family, was top priority prognostic signature for primary and metastatic melanoma progression-free survival and silencing USP10 markedly impairs the growth and metastatic potential of melanoma cells. We further uncover Forkhead box M1 (FOXM1) as a novel substrate of USP10. USP10 directly binds to FOXM1 and removes ubiquitin chains, thereby enhancing FOXM1 protein stability and driving melanoma progression. Notably, the lysine acetyltransferase KAT5 acetylates FOXM1 at residues K422 and K440, which strengthens the interaction between FOXM1 and USP10, facilitating deubiquitination and subsequent stabilization of FOXM1. Additionally, loss of either USP10 or FOXM1 suppresses the expression of the downstream target Telomerase reverse transcriptase (TERT), triggering cellular senescence. Importantly, we identify Golvatinib, as a novel inhibitor of USP10 that effectively curbs melanoma malignancy in both cellular and animal models. Taken together, these findings highlight the pro-tumorigenic role of USP10 in melanoma and suggest that disrupting the USP10/FOXM1 signaling axis could represent a viable therapeutic approach for treating this aggressive cancer.