MC1R loss-of-function variants are often associated with red hair, fair skin, and an increased risk of melanoma. By cooperating with Wellcome Trust Sanger Institute, we discovered that melanoma with MC1R loss of function variants bears a higher somatic mutation burden due to an impaired DNA damage repairability. These findings were published in Nature Communications 2015. Meanwhile, our work showed that palmitoylation, a common post-translational modification by covalent attachment of lipid, is essential for activating MC1R signaling. We identified that palmitoylation of MC1R is primarily mediated by the protein-acyl transferase ZDHHC13 and demonstrated that pharmacological activation of palmitoylation prevents melanomagenesis in the “red-haired” mouse model. These works were published in Nature 2017 and, for the first time, highlighted a central role for palmitoylation in protection against melanoma. Our subsequent work identified APT2 as the MC1R depalmitoylation enzyme and demonstrated that administration of the selective APT2 inhibitor ML349 treatment efficiently increases MC1R signaling under MC1R-RHC background and represses UVB-induced senescence and melanomagenesis in vitro and in vivo. Therefore, targeting APT2 represents a novel preventive/therapeutic strategy to reduce melanoma risk, especially in individuals with red hair. These findings were published in Nature Communications 2019. In addition, we also studied the role of DOT1-like histone H3K79 methyltransferase (DOT1L) in DNA damage repair and melanomagenesis. The manuscript of this work has been published in Nature Communications 2019. My research experience and my collaboration with global scientists have provided a solid foundation for me to progress into a leader in melanoma research and will further support me in achieving my long-term research goals.
In the United States, about 1/50 Americans are diagnosed with melanoma, and melanoma incidence increases at an estimated rate of 3% yearly. The Chen lab has primary research interests in the environmental and genetic factors contributing to melanoma development. One of our research is focusing on the reasons redheaded people are more likely to develop melanoma. Melanoma disproportionately affects redheads, as mutations in the melanocortin-1 receptor (MC1R), known to control the melanocyte cells producing pigment, make these redheads unable to tan or have pigmentation to protect their skin. Currently, the lab is using physiologically relevant animal models to study the role of MC1R in melanoma development. Expected outcomes will bring novel insights into the mechanisms of melanoma development and identify novel intervention strategies to combat melanoma.