The vitamin D hormone, 1,25dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and related compounds derived from vitamin D 3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8-oxo-7,8-dihydro-2 0 -deoxyguanosine (8-OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UVinduced DNA damage with 20-hydroxyvitamin D 3 or 24-hydroxylumisterol 3, as previously shown for 1,25(OH) 2 D 3 . Treatment with 1,25(OH) 2 D 3 reduced oxygen consumption rates in UV-exposed and sham-exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH) 2 D 3 . The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH) 2 D 3 and of naturally occurring CYP11A1-derived vitamin D-related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV-induced skin cancers, whereas mice lacking the 1αhydroxylase and thus unable to make 1,25(OH) 2 D 3 are not more susceptible.

PTEN is a well-known tumour suppressor protein that is frequently found to be mutated, inactivated or deleted in a wide range of different cancers. Its tumour suppressive properties result predominantly from its inhibitory effects on the PI3K-AKT signalling pathway. In melanoma, numerous different PTEN mutations have been identified in both melanoma cell lines and melanoma tissue. A number of different molecules can act on PTEN to either promote its suppression of melanoma, while other molecules may antagonise PTEN to inhibit its mechanism of action against melanoma. This review will discuss how the interactions of PTEN with other molecules may have a positive or negative impact on melanoma pathogenesis, giving rise to the potential for PTEN-targeted therapies against melanoma.

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