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Abstract
Some genetic melanocortin-1 receptor (MC1R) variants responsible for human red hair color (RHC-variants) are consequently associated with increased melanoma risk. Although MC1R signaling is critically dependent on its palmitoylation primarily mediated by the ZDHHC13 protein-acyl transferase, whether increasing MC1R palmitoylation represents a viable therapeutic target to limit melanomagenesis in redheads is unknown. Here we identify a specific and efficient in vivo strategy to induce MC1R palmitoylation for therapeutic benefit. We validate the importance of ZDHHC13 to MC1R signaling in vivo by targeted expression of ZDHHC13 in C57BL/6J-MC1RRHC mice and subsequently inhibit melanomagenesis. By identifying APT2 as the MC1R depalmitoylation enzyme, we are able to demonstrate that administration of the selective APT2 inhibitor ML349 treatment efficiently increases MC1R signaling and represses UVB-induced melanomagenesis in vitro and in vivo. Targeting APT2, therefore, represents a preventive/therapeutic strategy to reduce melanoma risk, especially in individuals with red hair.
Highlights
Some genetic melanocortin-1 receptor (MC1R) variants responsible for human red hair color (RHC-variants) are associated with increased melanoma risk
By using RNA sequencing (RNA-seq) data from the human The Cancer Genome Atlas (TCGA) melanoma cohort and GEPIA (Gene Expression Profiling Interactive Analysis)[24], we found that the mRNA levels of ZDHHC13 positively correlated with those of well-known targets downstream from MC1R signaling (Fig. 1a, b), including MITF and DCT25
We used TCGA clinical data and GEPIA24 and found that high mRNA levels of ZDHHC13 are associated with a survival benefit in melanoma patients (Fig. 1c). These results suggest that higher expression levels of ZDHHC13 is correlated with stronger activation of MC1R signaling in human melanomas
Summary
Some genetic melanocortin-1 receptor (MC1R) variants responsible for human red hair color (RHC-variants) are associated with increased melanoma risk. Human studies and mouse models have demonstrated that MC1R genetic variants are tightly correlated with phenotypes, such as red hair, fair skin, freckling, UV irradiation sensitivity, and melanoma risk. These variants are defined as red-hair-color (RHC) variants[2,3]. MC1R signaling plays an important role in promoting efficient DNA-damage repair[10,15,16,17,18,19,20] These observations raise a key question: can therapeutic intervention directed toward enhancing MC1R signaling reverse the increased melanoma risk associated with MC1R RHC variants?. We reveal that MC1R de-palmitoylation is catalyzed by APT2 and ML349, an APT2 inhibitor, rescues defects in MC1R RHC variant signaling and offers a potential avenue to an effective melanoma prevention strategy
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