Skin cancer is the most commonly diagnosed cancer in the United States; it is estimated that the number of Americans who have had a skin cancer in the last three decades is higher than the number for all other cancers combined. Fortunately, there are known prevention methods, effective treatments available for early-stage cases, and behavioral practices that can reduce the risk of secondary and recurrent cancer. However, in spite of these, skin cancer incidence continues to increase and mortality still exists, making skin cancer prevention of the utmost importance. Outlined in this dissertation are factors identify as associated with the development, diagnosis, and prognosis of skin cancer that could be targeted during primary, secondary, and tertiary skin cancer control and prevention interventions in Arizona. Utilizing the 2013 Arizona Behavior Risk Factor Surveillance System survey, aim one of this dissertation investigates factors associated with UVR exposure (as measured by sun protection use and sunburn history) that could be targeted during primary prevention efforts in order to reduce the disease burden. The results of this research are that approximately 20% of Arizona adults are protecting their skin with sunscreen or protective clothing every time they go outdoors and 28% of Arizona adults experienced one or more sunburns in the past 12 months. Compared with males, females were more likely to report that they protect their skin. Other factors associated with use of sun protection were higher education, higher income, good general health, and living in a more urban area. A recent history of sunburns was associated with being non-Hispanic white and a history of indoor tanning. Given that melanoma diagnosed in the earlier progression of the disease is associated with improved prognosis and significantly higher survival rates, secondary prevention interventions are essential to skin cancer control efforts. The second aim of this dissertation was to gain a better understanding of patient and community factors associated with late-stage melanoma diagnosis in Arizona. Based on Arizona Cancer Registry and community-level data, among melanoma patients there is evidence for significant associations between late-stage of diagnosis and being male (OR 1.22 [95%CI1.09-1.37]), non-white (OR 3.15 [95%CI 2.01-4.95]), and Hispanic (OR 2.13 [95%CI 1.61-2.81]). Additionally, access to care was found to influence stage of diagnosis. Residence in a rural area, compared to an urban area, was associated with late-stage melanoma diagnosis. Similarly, zip codes with a dermatologist density of less than 6 dermatologists per 100,000 persons, when compared to zip codes with greater than 12 dermatologists per 100,000 persons, were associated with late-stage melanoma diagnosis. A travel distance to the reporting hospital or clinic of over 40 miles, as compared to travel distance of 20 miles or less, was also associated with melanoma cases being diagnosed at a late-stage. Even after the progression of the disease, skin cancer survivors' prognosis and quality of life can be improved by following healthy lifestyle recommendations. The final aim of this study was to examine at what levels skin cancer survivors are meeting the recommended healthy lifestyle behaviors. Skin cancer survivors' behaviors were similar, with the exception of increased sun protection use, to behaviors among survivors of other non-skin forms of cancer. However, skin cancer survivors were more likely to practice healthy lifestyle behaviors than individuals without a reported history of cancer. Although skin cancer survivor did report better behaviors than non-cancer controls, there was still a considerable amount of survivors not practicing the recommended behaviors. Over 25% of skin cancer survivors only protected their skin during the summer or not at all. Additionally, low levels of other healthy lifestyle behaviors were noted among skin cancer survivors: slightly over half of skin cancer survivors met the physical activity recommendations, approximately half reported receiving their annual influenza vaccination, and less than 20% consumed 5 fruit or vegetable servings daily. This research suggests that there are opportunities for improved clinical and public health interventions targeted at increasing sun protection use, preventing sunburns, reducing disparities associated with late-stage melanoma, and improving healthy lifestyle behaviors among skin cancer survivors.

published_or_final_version / abstract / Anatomy / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Physiology / Master / Master of Philosophy

published_or_final_version / Chinese Medicine / Master / Master of Philosophy

published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

published_or_final_version / Community Medicine / Master / Master of Public Health

published_or_final_version / Public Health / Master / Master of Public Health

Epigenetic deregulation contributes significantly to the development of multiple human diseases, including cancer. While great effort has been made to elucidate the underlying mechanism, our knowledge on epigenetic regulation is still fragmentary, an important gap being how the diverse epigenetic events coordinate to control gene transcription. In the first part of our study, we demonstrated an important link between Snail-mediated transcriptional control and epigenetic regulation during cancer development. Specifically, we found that the highly conserved SNAG domain of Snail sequentially and structurally mimics the N-terminal tail of histone H3, thereby functions as a molecular “hook”, or pseudo substrate, for recruiting histone lysine specific demethylase 1 (LSD1) repressor complex to the E-cadherin promoter. Furthermore, we showed that Snail and LSD1 are both required for E-cadherin repression and EMT induction, and their expression is highly correlated with each other in multiple human tumor tissues. Our findings have important clinical ramifications in that compounds mimicking the SNAG domain may disrupt Snail-LSD1 interaction and inhibit EMT and metastasis. In the second part of our study, we designed a batch of compounds based on the structure of the SNAG domain and are currently screening for candidates capable of competing with SNAG peptide for LSD1 binding. In addition, we applied a peptide pulldown/mass spectrometry-coupled analysis to identify SNAG-interacting proteins, among which are many chromatin enzymes and modulators. Functional characterization of these proteins will help to elucidate the Snail-mediated epigenetic regulation process. In the third part of our study, we found that Snail interacts with poly(ADP-ribose) polymerase 1 (PARP1) through a potential pADPr-binding motif and is subject to poly(ADP-ribosyl)ation, which can stabilize the Snail-LSD1 complex for enhanced PTEN suppression under DNA damage condition. Our findings added another layer to the delicate Snail transcriptional machinery, and indicated that PARP inhibitors may be applied in combination with conventional chemotherapies to target cancers with high expression of Snail and LSD1. In summary, we demonstrated that Snail cooperates with multiple epigenetic machineries to induce EMT as well as survival of tumor cells. Our findings contribute to a better appreciation of Snail-mediated epigenetic network as well as diversification of therapeutic strategies against cancer.