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Cell signalling

Red alert about lipid's role in skin cancer

Nature volume 549, pages 337339 (21 September 2017) | Download Citation

Some versions of the MC1R protein are associated with red hair and an increased risk of developing a skin cancer called melanoma. It emerges that a lipid that binds MC1R might provide a target to reduce this risk. See Letter p.399

Red hair has long been a subject of fascination in many cultures, and it is increasingly capturing the attention of scientists. On page 399, Chen et al.1 report work in mouse models and human cells showing that the risk of skin cancer associated with certain versions of a protein connected to red hair can be reduced by increasing the degree to which this protein is modified by a lipid.

Melanocyte cells in the skin and hair follicles make a pigment called melanin, and can give rise to the deadly skin cancer melanoma. Melanin protects the skin against ultraviolet radiation from sunlight, which can cause DNA damage and possibly result in harmful mutations. The type of this pigment made by melanocytes is governed by the action of the MC1R protein. MC1R stimulation results in production of a dark form of melanin called eumelanin, but if MC1R signalling is low or absent, the primary type of melanin that is produced is a red or orange form called phaeomelanin (Fig. 1). Almost all red-haired individuals have a version of MC1R with reduced or absent signalling capacity, and most have fair skin that doesn't easily tan2.

Figure 1: Lipid link to skin cancer.
Figure 1

Using mouse models and human cells, Chen et al.1 studied the MC1R protein. Some versions of this protein are associated with red hair colour and linked to an increased risk of skin cancer12. The authors demonstrate that MC1R can bind fatty-acid molecules known as palmitates (a modification called palmitoylation), and show that this change can regulate the activity of the receptor. a, Wild-type MC1R exhibits higher levels of MC1R palmitoylation, which are associated with more-active receptor signalling, greater production of a melanin pigment called eumelanin rather than phaeomelanin, and the stimulation of DNA-repair pathways that can protect against DNA damage caused by ultraviolet rays. b, Some MC1R variants that the authors tested have lower palmitoylation, less-active MC1R signalling, greater production of phaeomelanin rather than eumelanin and less-efficient DNA repair than wild type, explaining the greater risk of skin cancer associated with such variants. Using a mouse model of skin cancer, the authors treated animals that carried an MC1R variant associated with red hair colour and an increased risk of skin cancer with a small molecule to increase MC1R palmitoylation (not shown). They found that this treatment slowed the rate of tumour formation. The authors suggest that drug treatment to target MC1R palmitoylation might have clinical benefit in some circumstances.

The MC1R gene was first identified in mice in which a loss-of-function mutation of the gene causes yellow fur3. 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 hair5: some variants almost always cause this coloration, whereas others have a weaker connection. 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 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 criterion. This finding is notable because if palmitate is attached to a protein in a process known as palmitoylation, it adds a hydrophobic component that enhances the 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 the receptor's activity.

MC1R is a member of a large family of cell-surface proteins called G-protein-coupled receptors, which share common cell-signalling mechanisms. 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 group 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 the site might be important for MC1R function.

Chen and colleagues demonstrated that MC1R is palmitoylated in human cells grown in vitro. They found that the level of palmitoylation increased in response to UV treatment and stimulation of the receptor by the peptide hormone α-MSH, which is produced by surrounding keratinocyte cells after UV damage. An increase in the level of palmitoylation of MC1R led to an increase in MC1R-mediated signalling and activation of the melanin-production pathway. The authors also tested an MC1R variant that cannot be palmitoylated; this receptor lacked signalling activity, whether or not it was stimulated by UV light. Notably, mice used by the authors that are engineered to have this MC1R variant are yellow, indicating the absence of MC1R function.

“Almost all red-haired individuals have a version of the MC1R protein with reduced or absent signalling capacity.”

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. When the authors increased or decreased the level of ZDHHC13 in cells, this respectively enhanced or reduced the level of both MC1R palmitoylation and receptor signalling in response to UV exposure. Furthermore, they found that the enzyme ATR — which is activated after DNA damage induced by UV exposure — responds to UV treatment by adding a phosphate group to ZDHHC13. Phosphorylation of ZDHHC13 leads to an increase in the interaction between ZDHHC13 and MC1R. This suggests a potential mechanism whereby UV damage of DNA could feed back to cause an increase in MC1R signalling, which the authors show can stimulate DNA 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 does so only in response to DNA damage.

To investigate whether enhanced 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. The authors observed that mice that also either lack MC1R or carry a common MC1R variant associated with red hair in humans develop tumours more rapidly after UV treatment than do the mice that have only the Braf mutation. However, before UV treatment, some mice with the MC1R variant were given a small molecule that increases palmitoylation. These animals developed tumours more slowly than did the MC1R-variant mice that had not received 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 synthesis of α-MSH, which activates MC1R in melanocytes9. The contribution of MC1R variants to the UV-damage response is multifaceted. First, cells with MC1R variants respond to α-MSH with less signalling activity than do cells that have wild-type MC1R, resulting in reduced eumelanin production, and therefore in a lower 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 generate more phaeomelanin, which can have a carcinogenic role, promoting melanoma formation11.

The observation that MC1R acts to protect against melanoma, and that an increase in MC1R palmitoylation enhances its function in both the wild-type and at least one partial loss-of-function variant, led the authors to suggest that increasing the palmitoylation status of MC1R in people with red hair might be a clinical strategy to prevent melanoma. Using sunscreen and trying to reduce sun exposure are well-established and usually effective measures for preventing skin cancer. However, the fact that individuals with MC1R variants have an increased risk of melanoma even when UV exposure is taken into account12 suggests that there might be merits in testing whether palmitoylation could be used to prevent melanoma. It has previously been suggested13 that another such strategy could be the use of drugs to enhance the signalling pathway downstream of MC1R, but this would activate a protective tanning response by melanocytes, even in the absence of UV exposure. Chen and colleagues' work reveals that increasing palmitoylation of MC1R could induce an MC1R response specifically as a consequence of UV exposure.

This effect may be specific to the given MC1R variant because it has been shown previously14 that some MC1R red-hair variants, including one tested by Chen and colleagues, have reduced signalling ability because they fail to localize correctly to the cell membrane. It is possible that these variants may be especially amenable to enhancement by palmitoylation, whereas others, which reach the cell surface but fail to signal, would not be enhanced by an increase in palmitoylation.

From a medical viewpoint, intervention to treat common genetic variation in healthy individuals is unlikely to be desirable. Moreover, people without red hair who carry a single copy of a variant MC1R gene have a raised melanoma risk15. Individuals who have an MC1R variant gene make up more than half of the northern European population15. Preventive treatment on this population-scale level seems unlikely. Nevertheless, the potential to stimulate DNA-repair pathways in melanocytes after UV damage, especially in people who lack MC1R, is an important concept for preventing onset of melanoma. Therapeutic intervention through activation of MC1R might therefore be appropriate in some clinical contexts.

Interestingly, many natural products contain palmitates. A palmitic-acid ester in oil from the lotus flower (Nelumbo nuficera) enhances melanin production when added to melanocytes grown in vitro16. Coconut oil is also rich in palmitates. Perhaps it is time to investigate the anecdotal claims that coconut oil can help you to tan?

Notes

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  1. Ian J. Jackson and E. Elizabeth Patton are in the MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK.

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Correspondence to Ian J. Jackson or E. Elizabeth Patton.

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