AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis

The study explored the role of AMP-activated protein kinase (AMPK) in enhancing melanocortin-1 receptor (MC1R) activity to suppress melanoma development, particularly in individuals with red hair, who are at higher risk due to genetic variations. AMPK phosphorylated ZDHHC13 at S208, which increased the interaction with MC1R-RHC, leading to enhanced MC1R palmitoylation and downstream signaling. This process repressed UVB-induced transformation of human melanocytes in vitro and delayed melanomagenesis in C57BL/6J-MC1R-RHC mice. The study also found that AMPK upregulation in human melanomas correlated with factors downstream from MC1R signaling and improved patient survival, suggesting that AMPK activation could be a promising strategy to reduce melanoma risk in red-haired individuals.