Elucidating the Roles of Metabolic and Pigment-Modulating Factors in Melanoma
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Hsiao, Jennifer Jia-An
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CitationHsiao, Jennifer Jia-An. 2019. Elucidating the Roles of Metabolic and Pigment-Modulating Factors in Melanoma. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractMetastatic melanoma is a deadly form of skin cancer that arises from the malignant transformation of melanocytes, the pigment-producing cells of the skin. Genetic and environmental factors both play a role in susceptibility to the disease. Alterations in the genome that lead to deletion or silencing of tumor suppressors or activation of oncogenes can result in increased melanomagenesis.
Methylthioadenosine phosphorylase (MTAP) plays a key role in methionine and adenine salvage pathways. It is present in virtually all normal tissues but often lost or silenced in cancer. In chapter 2, I present a novel mechanism in which MTAP acts as a tumor suppressor in melanoma by moderating expression of microphthalmia-associated transcription factor (MITF), a master transcriptional regulator of melanocytes that can become an amplified or mutated oncogene in melanoma.
Individuals with the red hair color (RHC) phenotype are at the highest risk of developing melanoma, compared to individuals with other skin phototypes. The RHC phenotype results from inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene, which result in production of mainly the red/yellow pigment pheomelanin. Increased MC1R activity induces the production of brown/black eumelanin. Although ultraviolet (UV) radiation plays a role in melanomagenesis, it has been shown in RHC mice that there is also a UV-independent, pheomelanin-dependent mechanism for melanomagenesis.
We hypothesized that upregulating the pheomelanin synthesis pathway would increase melanomagenesis in RHC mice, which produce mainly pheomelanin and very little eumelanin. L-DOPA, an intermediate in the pigment synthesis pathway, is a drug commonly taken by Parkinson’s disease patients. In chapter 3, I show that RHC mice that were treated with L-DOPA developed melanoma at a faster rate than control RHC mice. The effect of increased melanomagenesis in L-DOPA-treated mice was abolished when melanin production was ablated or when eumelanin was introduced.
Because data previously suggested an oxidative damage mechanism for the increased UV-independent, pigment-dependent melanomagenesis in RHC mice, we hypothesized that antioxidants could protect against melanomagenesis. In chapter 4, I show that the antioxidant N-acetylcysteine (NAC) paradoxically increases melanomagenesis in the RHC context. This effect was abolished when melanin production was ablated.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42029583
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