DELINEATING THE ROLE OF THE HOMOCYSTEINE-FOLATE-THYMIDYLATE SYNTHASE AXIS AND URACIL ACCUMULATION IN AFRICAN AMERICAN PROSTATE TUMORS - African American prostate cancer patients are known to be diagnosed at an earlier age, present with aggressive disease, and are twice as likely to succumb to prostate cancer than other demographic groups. Despite a major focus on socioeconomic factors, recent findings strongly argue for the existence of biological factors driving cancer disparities. In my efforts to understand biological drivers in prostate cancer, I applied a novel DNA damage detection method, Repair Assisted Damage Detection (RADD), and established that African American tumors have more DNA lesions overall than EA tumors, especially uracil lesions. Our lab has previously demonstrated that the homocysteine-methionine pathway is a metabolic hallmark of African American prostate cancers, which fuels the progression of the folate cycle that is required for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). An upregulation of metabolites in the de novo pyrimidine biosynthesis pathway and altered levels of folate cycle metabolites were identified in African American prostate tumors, suggesting the link between uracil metabolism and uracil lesion accumulation. Uracil lesions are repaired by the base excision repair pathway. We have also shown that expression of XRCC1, a protein involved in coordinating base excision repair function, was lower in African American prostate tumors, indicative of defective base excision repair. These data collectively suggest that African American tumors exhibit the consequences of thymidylate stress, where the ability of thymidylate synthase (TYMS) to convert dUMP to dTMP is obstructed, resulting in dysregulation of base excision through the retention of uracil lesions. The increased amounts of uracil lesions in African American men could be a cumulative result of changes in nucleotide metabolism, which is caused by altered levels of components in the folate cycle and one-carbon metabolism. These components, such Vitamin B12 and folate, are known to be reduced in African American men, which could result from either dietary deficiencies or due to an aberrant homocysteine-methionine cycle, or both. While we understand the molecular consequences of reduced folate as it relates to uracil accumulation, the circumstances surrounding the DNA damage response through the regulation of Vitamin B12 and folate is currently unknown. The hypothesis of this proposal is that altered levels of Vitamin B12 and folate contribute to thymidylate stress, resulting in base excision repair pathway dysfunction and promoting prostate cancer progression in African American men. In this proposal, we will 1) determine the clinical relevance of homocysteine, Vitamin B12, and folate with prostate cancer progression in African American men and 2) elucidate the role of homocysteine, Vitamin B12, and folate regulation on TYMS function and base excision repair in African American prostate cancer patients. Successful completion of these aims will establish a link between metabolism and DNA repair in African American men with prostate cancer and help develop metabolic biomarkers to stratify these patients for DNA repair inhibitor therapies.
