Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, 250014, Jinan, Shandong, China.
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA.
Nat Commun. 2019 Feb 20;10(1):877. doi: 10.1038/s41467-019-08691-3.
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 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.
一些导致人类红头发颜色（RHC-变体）的遗传黑色素皮质素-1 受体（MC1R）变体与黑色素瘤风险增加有关。尽管 MC1R 信号主要依赖于其棕榈酰化，主要由 ZDHHC13 蛋白酰基转移酶介导，但增加 MC1R 棕榈酰化是否代表限制红发人群黑色素瘤发生的可行治疗靶点尚不清楚。在这里，我们确定了一种特定且有效的体内策略来诱导 MC1R 棕榈酰化以获得治疗益处。我们通过在 C57BL/6J-MC1R 小鼠中靶向表达 ZDHHC13 来验证 ZDHHC13 对体内 MC1R 信号的重要性，随后抑制黑色素瘤发生。通过鉴定 APT2 为 MC1R 脱棕榈酰化酶，我们能够证明选择性 APT2 抑制剂 ML349 的给药可有效增加 MC1R 信号，并抑制体外和体内 UVB 诱导的黑色素瘤发生。因此，靶向 APT2 代表了一种预防/治疗策略，可以降低黑色素瘤风险，特别是在红发人群中。
