Letter | Published:

Palmitoylation-dependent activation of MC1R prevents melanomagenesis

Nature volume 549, pages 399403 (21 September 2017) | Download Citation

Abstract

The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation1,2,3,4,5,6,7,8. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH)9 stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation10,11,12,13,14,15,16. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma5,17,18,19,20. However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1re/eJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.

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Acknowledgements

We thank X. Yao, H. Xie and G. Wei for careful reading and suggestions. This work was supported by the National Institutes of Health (R.C.: R01CA137098, R01CA193913 and R01CA196896), Department of Defense (R.C., CA140020), Melanoma Research Foundation Establish Investigator Award (R.C.), Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (R.C., 81428025), National Natural Science Foundation of China (X.G., 81630106), and the Ludwig Institute for Cancer Research (C.R.G.). R.C. is an American Cancer Society Research Scholar.

Author information

Author notes

    • Shuyang Chen
    • , Bo Zhu
    •  & Chengqian Yin

    These authors contributed equally to this work.

Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA

    • Shuyang Chen
    • , Bo Zhu
    • , Chengqian Yin
    • , Wei Liu
    • , Changpeng Han
    • , Xin Li
    •  & Rutao Cui
  2. Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA

    • Baoen Chen
    •  & Xu Wu
  3. Jinan University Institute of Tumor Pharmacology, Guangzhou, Guangdong 510632, China

    • Tongzheng Liu
  4. Hunan Key Laboratory of Skin Cancer and Psoriasis/Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China

    • Xiang Chen
  5. Department of Dermatology, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710000, China

    • Chunying Li
  6. Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China

    • Limin Hu
    •  & Xiumei Gao
  7. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China

    • Jun Zhou
  8. Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

    • Zhi-Xiang Xu
  9. Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford OX3 7DQ, UK

    • Colin R. Goding

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Contributions

R.C. conceived the hypothesis, organized and supervised the study. R.C. designed the project with help from S.C., B.Z. and C.Y. S.C., B.Z. and C.Y. analysed and interpreted data. S.C. performed mouse experiments (melanomafree survival, histopathology) with assistance from C.Y. B.Z. independently reproduced mouse experiments with assistance from W.L. and C.H. S.C. performed protein palmitoylation assays. B.Z. and C.Y. independently reproduced protein palmitoylation assays with assistance from W.L. and C.H. S.C. performed melanocytes function (cAMP, MITF, DNA repair, senescence) measurement and cellular transformation assay, which were independently reproduced by C.Y. B.C. and X.W. designed and performed the transfection of HA–ZDHHC, which was independently reproduced by S.C. and C.Y. T.L., X.L., X.C., C.L., L.H., J.Z., Z.X., X.G. and C.R.G. contributed to data analysis, interpretation and revision of the manuscript. R.C. wrote the manuscript with help from C.R.G. All authors commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rutao Cui.

Reviewer Information Nature thanks G. Merlino and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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DOI

https://doi.org/10.1038/nature23887

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