ZDHHC4-mediated ZEB-2 S-palmitoylation promotes melanoma epithelial-mesenchymal transition via deubiquitinating and stabilizing ZEB-2

ZDHHC4, a palmitoyl transferase belonging to the DHHC family, is crucial in cells by catalyzing palmitoylation of proteins, thereby regulating their function and localization. However, its role in melanoma is not well understood. Here, our research determined that ZDHHC4 expression was upregulation in human melanoma specimens and cells. Functional studies reveal that knocking down ZDHHC4 inhibits cell proliferation, migration and invasion of melanoma cells. Moreover, we performed mass spectrometry analysis and found that ZEB-2 is a substrate of ZDHHC4. ZEB-2 interacted with ZDHHC4 through its N-terminal sequences, which promotes the ZDHHC4-mediated palmitoylation of ZEB-2 at C478, facilitating ZEB-2 deubiquitination and its protein stability. This key modification is required for epithelial-to-mesenchymal transition (EMT) in melanoma cells. Furthermore, we found a positive correlation between the expression levels of ZDHHC4 and ZEB-2 in clinical melanoma samples. In summary, our results provide a deeper understanding of mechanism regulating ZDHHC4 in melanoma, suggesting that targeting ZDHHC4 may offer novel therapeutic strategies by suppressing tumor growth and metastasis through the disruption of ZEB-2 palmitoylation process.