Cell Signalling Reducing melanoma risk for redheads?

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Cell Signalling

Reducing melanoma risk for redheads?

Some versions of the MC1R receptor protein are associated with red hair and a higher risk of developing a skin cancer called melanoma. It emerges that a lipid that binds MC1R might provide a new opportunity to reduce this risk in red hair individuals. See Letter p.XXX

Ian J. Jackson & E. Elizabeth Patton

Red hair has long been a subject of fascination in many cultures, and it is increasingly capturing the attention of scientists too. In a paper online in Nature, Chen et al.1 use mouse models and human cells to discover how the risk of skin cancer due to versions of a protein associated with red hair can be reduced by increasing the modification of the protein by a lipid.

Melanocyte cells in the skin and hair follicles make a pigment called melanin that protects the skin against ultraviolet (UV) radiation from sunlight, which can cause DNA damage and possibly give rise to harmful mutations, and melanocytes are the cell of origin of the deadly skin cancer called melanoma. The type of melanin pigment made by melanocytes is governed by the action of the MC1R receptor protein. MC1R stimulation results in production of a dark form of melanin called eumelanin, but if MC1R signalling is low or absent, a red or orange form of melanin called phaeomelanin forms instead. Almost all red-haired individuals have an MC1R version that has reduced or absent signalling capacity, and as well as red hair, these individuals also usually have fair skin that doesn’t easily tan.

The MC1R gene was first identified in mice in which a loss-of-function mutation of the gene results in yellow fur2. Certain versions of the human MC1R gene are associated with red hair3. Many other species also have pigment alterations associated with specific versions of MC1R, as is the case, for example, in dogs with red or yellow coats4. Humans who have ancient European ancestry often have variant forms of MC1R, and these differ in the strength of their association with red hair,5 some almost always cause red hair, whereas others have a weaker association with red hair. MC1R variation is necessary, but not always sufficient, to produce red hair, suggesting that most variants retain some signalling activity that may be masked or enhanced depending on other genetic or cellular factors5.

Chen et al. conducted a screen using human melanocytes grown in vitro to try to identify molecules that enhanced the level of signalling downstream of MC1R in some versions of the protein that are associated with red hair. They found that the fatty acid molecule palmitate met this criteria. This finding is notable because if palmitate is attached to a protein in a process known as palmitoylation, this presence of an additional hydrophobic component would enhance a protein’s interaction with the cell membrane. It is probable that such a change would increase MC1R targeting to or time spent at the cell surface and thereby could be a mechanism to regulate its activity.

MC1R is a member of a large family of cell-surface receptor proteins called G-protein-coupled receptors (GPCRs), which share common mechanisms of cell signalling, and many of these receptors are known to be palmitoylated. Although MC1R had not previously been shown to be modified in this way, it has an amino-acid motif near its carboxy terminus that is characteristic of a palmitoylation site. Moreover, red and yellow dogs that lack MC1R signalling have a mutation that removes this site from the protein4, suggesting that it might be important for MC1R function. Testing human cells grown in vitro. Chen and colleagues demonstrated that MC1R is palmitoylated. In response to UV treatment, they found that the level of palmitoylation increased, leading to an increase in MC1R-mediated signalling and in activation of the melanin production pathway. However, an MC1R variant they tested which lacks the palmitoylation motif was not palmitoylated, and this receptor lacked signalling activity, whether it was stimulated or not by ultraviolet light. Notably, mice with MC1R mutated in the palmitoylation motif are yellow indicating absence of MC1R function.

Palmitoylation is mediated by a family of palmitoyl transferase enzymes called ZDHHC proteins. By testing a panel of these proteins for their ability to modify MC1R in cells, Chen and colleagues identified ZDHHC13 as an enzyme that might be responsible for MC1R palmitoylation. If the authors increased or decreased the level of ZDHHC13 in cells, this respectively enhanced or reduced the level of both MC1R palmitoylation and the receptor signalling in response to UV exposure. Furthermore, they found that the enzyme ATR, which is activated following DNA damage induced by UV exposure, responds to UV treatment by adding a phosphate group to ZDHHC13. Phosphorytion of ZDHHC13 leads to an increase in the interaction between ZDHHC13 and MC1R. This suggests a potential mechanism by which UV damage of DNA could feedback to cause in an increase in MC1R signalling, which they show stimulates DNA-damage repair. However, a possible problem with this model is that mice that have ZDHHC13 mutations do not seem to have MC1R defects; and although they have some hair growth defects, their hair colour is unaffected by the mutation6,7. Perhaps another ZDHHC family enzyme modifies MC1R in vivo or ZDHHC13 only modifies MC1R in response to DNA damage.

To investigate whether an enhancement of MC1R palmitoylation could affect melanoma formation, the authors used a mouse model in which melanocytes contain a BRAF gene alteration that increases the probability that melanoma will arise in response to UV exposure8. Using this system, mice which also either lack MC1R or carry a common MC1R variant associated with human red hair colour, develop tumours more rapidly following UV treatment compared to the mice which have the BRAF mutation alone However, if before UV treatment the mice that contain the MC1R variant are given a small-molecule which increases palmitoylation, their tumour formation is delayed compared to that in the MC1R variant mice which did not receive the small molecule.

It has previously been shown9 that the response of mouse melanocytes to UV can be mediated by neighbouring keratinoctyte cells in the skin, which respond to DNA damage by producing the protein p53. This in turn induces the synthesis of the peptide hormone αMSH, which activates MC1R in melanocytes9. The contribution of MC1R variants to the UV-damage response is multifaceted. First, compared to wild-type MC1R cells, MC1R variants have reduced signalling activity in response to αMSH, resulting in lower levels of eumelanin production (a lower tanning tanning response and failure to protect the skin from further UV damage). Second, MC1R variants are less able to stimulate the DNA repair in melanocytes that can protect the genome from cancer-causing mutations10. Finally, MC1R variants have increased generation of phaeomelanin, which can have a carcinogenic role in melanoma formation11

In whichever way MC1R protects against melanoma, an increase in MC1R palmitoylation enhances the function of both ancestral and (at least one) partial loss-of-function variant. This observation led the authors to suggest that increasing the palmitoylation status of MC1R in red-haired individuals might be a possible clinical strategy to try to prevent melanoma. It has previously been suggested12 that a potential strategy to reduce melanoma in red-haired individuals could be the use of drugs to enhance the signalling pathway downstream of MC1R, however, this approach would activate a protective tanning response of melanocytes even in the absence of UV exposure. Chen and colleagues’ work reveals that increasing palmitoylation of MC1R could offer an approach to induce a tanning response that specifically occurs only as a consequence of UV exposure.

Using sunscreen lotion and trying to reduce sun exposure are well-established and usually effective skin-cancer preventative measures. However, individuals who have MC1R variants have a higher risk of melanoma even when UV exposure is taken into account13, which suggests that there might be merits in testing whether palmitoylation could be used as a preventative strategy for melanoma. It has been shown previously that some MC1R red-hair variants (including the one tested here) have reduced signalling ability because they fail to localise properly to the cell membrane. It is possible that these variants may be especially amenable to enhancement by palmitoylation, whilst others, which reach the cell surface but fail to signal, will not be enhanced14.

From a medical viewpoint, intervention to treat common genetic variation in healthy individuals is unlikely to be desirable. Further considerations include non-red haired individuals who carry a single copy of a variant MC1R gene do not have red hair, but do have raised melanoma risk. These individuals make up over a third of the Northern European population15. Preventative treatment at this type of population scale seems an unlikely prospect. Nonetheless, the potential to stimulate DNA damage repair pathways in melanocytes following UV damage, especially in MC1R deficient individuals, is an important concept to prevent melanoma onset, and therapeutic intervention through activation of MC1R may be appropriate in some clinical contexts.

Interestingly, many natural products contain palmitates. A palmitic acid ester in oil from the lotus flower enhances melanin production when added to melanocytes grown in vitro16. Coconut oil is also rich in palmitates. Perhaps there is some truth in the anecdotal claims that coconut oil can help you to tan?

Ian J. Jackson and E. Elizabeth Patton are in the MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH42XU, UK.

e-mail: ian.jackson@igmm.ed.ac.uk; liz.patton@igmm.ed.ac.uk

1. Chen et al. Nature23887 (2017).

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4. J. M. Newton, et al. Melanocortin 1 receptor variation in the domestic dog. Mamm Genome 11, 24-30 (2000).

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6. A. N. Saleem, et al. Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase. PLoS Genet 6, e1000985 (2010).

7. C. J. Perez, et al. Increased Susceptibility to Skin Carcinogenesis Associated with a Spontaneous Mouse Mutation in the Palmitoyl Transferase Zdhhc13 Gene. J Invest Dermatol 135, 3133-3143 (2015).

8. D. Dankort, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41, 544-552 (2009).

9. R. Cui, et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 128, 853-864 (2007).

10. J.E. Hauser, et al. Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes. Pigment Cell Res. 19 303-14 (2006)

11. D. Mitra, et al. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 491 449-53 (2012).

12 J. A. D'Orazio, et al. Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature 443, 340-344 (2006).

13. J. Wendt, et al. Human Determinants and the Role of Melanocortin-1 Receptor Variants in Melanoma Risk Independent of UV Radiation Exposure. JAMA Dermatol 152, 776-782 (2016).

14. K.A. Beaumont et al. Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. Hum Mol Genet. 14 2145-54

15. E. Tagliabue, et al. MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project. Br J Cancer 113 354-63 (2015)

16. S. Jeon, N. H. Kim, B. S. Koo, J. Y. Kim, A. Y. Lee, Lotus (Nelumbo nuficera) flower essential oil increased melanogenesis in normal human melanocytes. Exp Mol Med 41, 517-525 (2009).

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