Ubiquitin E3 ligase KPC1 governs mesenchymal metastatic melanoma reprogramming via proteasomal degradation of ZEB1

Metastatic melanoma (MM) displays remarkable phenotypic plasticity, allowing tumor cells to transition reversibly between proliferative and mesenchymal (MES)-like states. This dynamic switching is strongly associated with therapeutic resistance and poor prognosis. Although transcriptional and epigenetic mechanisms driving these transitions have been extensively studied, the role of post-translational regulation, particularly the ubiquitin-proteasome system, remains poorly understood. Here, we identify the ubiquitin E3 ligase RNF 123 (KPC1) as a key post-translational suppressor of MES reprogramming in MM. Integrative analyses of bulk and single-cell transcriptomic datasets revealed that KPC1 expression is inversely correlated with the expression of core mesenchymal markers such as ZEB1, CDH2, and AXL, and positively associated with epithelial and melanocytic lineage genes, including CDH1 and MITF. Deconvolution of TCGA-SKCM RNA-seq data confirmed that this inverse correlation is specific to malignant melanoma cells and strongest in tumors enriched for mesenchymal gene signatures. Single-cell trajectory and enrichment analyses further demonstrated that decreasing KPC1 expression accompanies MES-like switch. Mechanistically, KPC1 binds and promotes the ubiquitination and proteasomal-mediated degradation of ZEB1, thereby suppressing cadherin switching and cell motility. Loss of KPC1 in melanoma cells prevented ZEB1 proteasomal-mediated degradation, increased expression of mesenchymal markers, and enhanced MM cells migration. Clinically, low KPC1 protein levels were associated with increased expression of ZEB1 and CDH2 and poorer overall survival. Furthermore, combined assessment of KPC1, ZEB1, and CDH2 expression improved patient stratification, suggesting the potential utility of multi-marker signatures for prognostic modeling. These findings establish KPC1 as a central post-translational regulator of melanoma cell state plasticity through targeted degradation of ZEB1. This study highlights a novel mechanism regulating MES-like transition and highlights KPC1 as a potential theragnostic target in MM.