Epigenetic Reprogramming and Skin Cancer Prevention
Abstract
Ultraviolet (UV) radiation (natural sunlight and artificial sources) significantly increases risk of skin cancers, squamous cell carcinoma (SCC), and melanoma. Studies have shown that the U.S. military and general populations have significant differences in incidence of skin cancers, and one recent study reveals that Soldiers deployed to sunny climates are especially prone to development of these common and potentially fatal skin cancer types. Currently, the incidence of melanoma alone in U.S. general populations is 53,599 per year. SCC is considerably more common, accounting for an average annual cost of over $8 billion/year in the U.S. Individuals in the Armed Forces who serve in topical areas and receive heavy sun exposure for several years during early adulthood may be at significantly higher (>five-fold) risk for the development of cutaneous malignant melanoma and SCC later in life. Adding to this, recent data suggest that melanoma incidence has increased in both populations, with the most rapid increase (40%) among younger men in the military. In civilian settings, melanoma is occurring at earlier ages, in part related to use of tanning beds that when used before age 30 increase melanoma risk by 75%. We are concerned in this study with how the ?epigenome,? composed of a variety of specific chemicals that surround DNA and tell it what to do without changing the DNA sequence, may cause skin cancer. Our research group has published a landmark study that investigates in melanoma a novel epigenomic DNA hydroxymethylation mark named 5-hmC, a human genome ?tag,? which can be turned ON or OFF by microenvironmental changes. Many studies have shown that the 5-hmC ?tag? may serve as a biomarker for the progression of aggressive tumors, including brain, bowel, skin, and ovarian cancer. Most importantly, we were able to develop treatments that reverse the epigenetic defect and successfully blocked the growth of tumor cells in animal models. In this study, we propose to explore 5-hmC as a key functionally important epigenetic aberration in SCC and melanoma and as a sensitive biomarker to predict and estimate malignant transformation early on in skin cells. Ultimately, we propose to prevent skin cancers by manipulating DNA hydroxymethylation modulators via blocking malignant transformation at initial stages. Thus, our ultimate goal is to prevent and reverse SCC and melanoma by targeting such tumors using a novel epigenetic reprogramming strategy. This proposed study will benefit military personnel as well as the general population in multiple ways. Short term, it will prove that the 5-hmC DNA ?tag? is a sensitive biomarker to predict skin cancer development at the very earliest stages that cannot be detected clinically. We aim to develop an easily applicable method to detect the DNA ?tag? in patient samples in relationship to the key carcinogenic effects induced by UV radiation. This study will further compare and contrast the global 5-hmC genomic landscape between normal skin cells (keratinocytes and melanocytes) and their malignant counterparts (SCC and melanoma cells). The long-term impact of this proposed study is critical because it will develop new strategies to prevent and reverse skin cancer initiation at the level of the ?epigenome.? The proposed studies are within the stated mission and goals of the Department of Defense to increase our knowledge in the field of cancer with early tumor diagnosis and screening and reduce cancer mortality rates through better, less toxic therapies. Data collected from these key studies could be instrumental in the design of new approaches to prevent skin SCC and melanoma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710318
Entities
People
- Christine Lian
Organizations
- United States Army