Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads
Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads
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靶向 MC1R 去棕榈酰化以预防红发黑色素瘤生成
DOI：
10.1038/s41467-019-08691-3
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发表时间：
2019-02-20
影响因子：
16.6
通讯作者：
Cui, Rutao
中科院分区：
文献类型：
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作者：
Chen, Shuyang;Han, Changpeng;Cui, Rutao
因此，一些遗传性黑皮质素-1受体（MC 1 R）变异体（RHC变异体）与黑色素瘤风险增加有关。尽管MC 1 R信号传导主要依赖于其棕榈酰化，主要由ZDHHC 13蛋白酰基转移酶介导，但增加MC 1 R棕榈酰化是否代表限制红发人黑色素瘤发生的可行治疗靶点尚不清楚。在这里，我们确定了一个具体的和有效的体内策略，以诱导MC 1 R棕榈酰化的治疗效益。我们通过在C57 BL/6 J-MC 1 R（RHC）小鼠中靶向表达ZDHHC 13并随后抑制黑色素瘤生成来验证ZDHHC 13对MC 1 R信号传导的体内重要性。通过鉴定APT 2作为MC 1 R去棕榈酰化酶，我们能够证明，管理的选择性APT 2抑制剂ML 349治疗有效地增加MC 1 R信号传导和抑制UVB诱导的黑色素瘤在体外和体内。因此，靶向APT 2代表了降低黑色素瘤风险的预防/治疗策略，特别是在红发个体中。
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-MC1R(RHC) 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.