Dermokine mutations contribute to epithelial-mesenchymal transition and advanced melanoma through ERK/MAPK pathways

Abstract

Abstract In the present study, the vulnerability associated with dermokine (DMKN), as a new trigger for the Epithelial-Mesenchymal Transition (EMT)-driven melanoma, was assessed based on a genome-wide genetic screening using transgenic. The results suggested a significantly higher DMKN expression in human Malignant Melanoma (MM), which was correlated with poor overall survival among melanoma patients, especially BRAF-mutated MM samples. Additionally, an in vitro knockdown of DMKN inhibited the cell proliferation, invasion, and apoptosis of MM cancer cells by activating ERK/MAPK signaling pathways and regulating STAT3 in downstream molecules. The interrogation of in vitro melanoma dataset and characterization of advanced melanoma samples revealed that DMKN downregulated the EMT-like transcriptional program through disrupting MET/EMT cortical actin, enhanced the expression of epithelial markers, and decreased that of mesenchymal markers. Whole-exome sequencing was presented with p.E69D and p.V91A DMKN mutations as novel somatic loss-of-function mutations. Further, the purposeful proof-of-principle modeled the interaction of ERK with p.E69D and p.V91A DMKN mutations in the ERK-MAPK kinase signaling that may be naturally associated with the EMT triggering during the melanomagenesis. These results provided preclinical evidence for the role of DMKN in shaping the EMT-like melanoma phenotype and introduced DMKN as a new exceptional responder to personalized MM therapy.