Variants in Hdac9 Intronic Enhancer as Candidates for Skin Tumor Susceptibility Locus
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Series/Report no.:2014 Richard J. and Martha D. Denman Undergraduate Research Forum. 19th
Non-melanoma skin cancers (NMSC) are the most common forms of cancer in the world accounting for nearly half of all cancer diagnoses. Rates of NMSC are on the rise with an over 300% increase in diagnosis of these cancers in the last 20 years. While environmental risk factors for skin cancers are well understood, little is known about genetic risk factors for these cancers. Mouse linkage studies have identified several loci housing skin cancer susceptibility genes. Human tumors show evidence of preferential allelic imbalance for polymorphisms in Hdac9, a gene mapping to one of the linkage regions, Skts5. One intron in the Hdac9 gene between exons 8 and 9 contains an enhancer for Twist1, affecting limb development and phenotypes in the skin. Twist1 is a known regulator of skin differentiation and has a documented role in cancer. The hypothesis of this study is that this enhancer locus plays a role in the differential risk for NMSC between the cancer susceptible NIH/Ola and cancer resistant Spretus/EiJ mice. Sequence analyses identified several polymorphisms between these strains in this intron which are predicted by in silico methods to disrupt transcription factor binding. To investigate in vitro effects of these variants, intron fragments from both NIH/Ola and Spret/EiJ murine DNA were cloned into an enhancer reporting PGL3 vector and transfected into both normal keratinocyte C5N and squamous cell carcinoma A5 cells. Luciferase assay and real-time PCR data suggest these variants are responsible for changes in gene expression, specifically in the Twist1 gene. Chromatin Immunoprecipitation studies are being performed to test whether transcription factors, Oct1 and Gata3 that are predicted to differentially bind the NIH/Ola and Spret/EiJ enhancer , are involved in the differential Twist1 expression. This project has the potential implication of discovering the role a specific gene locus, Skts5, plays in NMSC risk.
Health Professions - Laboratory/Cellular: 3rd Place (The Ohio State University Denman Undergraduate Research Forum)
Academic Major: Biomedical Science
College of Health and Rehabilitation Sciences: Honors Thesis Scholarship
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