Palmitoylation-deficient MC1R variants accelerate BRAFV60E-driven melanomagenesis.

  • Major finding: Palmitoylation-deficient MC1R variants accelerate BRAFV60E-driven melanomagenesis.

  • Mechanism: ZDHHC13 directly binds to and palmitoylates MC1R in response to UV radiation.

  • Impact: Pharmacologic activation of MC1R palmitoylation may protect against the development of melanoma.

The G-protein–coupled receptor melanocortin-1 receptor (MC1R) is expressed on melanocytes and involved in regulating pigmentation. The α-melanocyte–stimulating hormone (α-MSH) activates MC1R to promote cAMP signaling, melanin production, and DNA repair after ultraviolet radiation (UVR). MC1R variants, especially variants linked to red hair, fair skin, and poor tanning ability (termed RHC variants), are associated with an increased risk of melanoma, but it is unclear if restoration of MC1R activity could have therapeutic benefit in individuals with RHC variants. Chen, Zhu, Yin, and colleagues found that palmitic acid, but not other lipids, increased cAMP levels in primary melanocytes with an MC1R R151C RHC variant, suggesting that palmitoylation may promote MC1R activity. Accordingly, a palmitoylation inhibitor blocked the palmitic acid–mediated increase in cAMP. In the presence of α-MSH, MC1R was palmitoylated by the palmitoyl acyltransferase ZDHHC13, but the MC1R variants R151C and R160W displayed reduced palmitoylation and decreased downstream MC1R signaling. Mechanistically, UVR promoted ATR-mediated phosphorylation of ZDHHC13, increasing the association between ZDHHC13 and MC1R, and enhancing MC1R palmitoylation. The MC1R RHC variants promoted BRAFV60E-mediated transformation of melanocytes in colony-formation assays, which was reversed by rescuing palmitoylation via overexpression of ZDHHC13. Further, ZDHHC13 overexpression suppressed MC1R R151C–augmented BRAFV60E-mediated transformation in xenografts. In MC1R loss-of-function mice (Mc1re/eJ), the MC1R R151C variant produced accelerated melanomagenesis, which was suppressed by pharmacologic activation of palmitoylation using the deacylating enzyme inhibitor palmostatin B. Thus, palmostatin B extended survival. In addition to suggesting a role for MCR1 palmitoylation in protecting against melanoma, these findings provide a mechanism by which RHC variants can suppress palmitoylation to increase melanoma risk, and suggest the possibility for therapeutic reactivation of MC1R palmitoylation.

Chen S, Zhu B, Yin C, Liu W, Han C, Chen B, et al. Palmitoylation-dependent activation of MC1R prevents melanomagenesis. Nature 2017 Sep 6 [Epub ahead of print].

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