Hyperglycemia-Mediated Transcriptional Alterations in Tumorigenesis

The relationship between metabolism and cancer is formed through molecular mechanisms which allow for the growth of all cells in our body. Unfortunately, cancer cells rely on similar growth pathways found in normal healthy cells but reprogram them to adopt a cellular growth advantage. Recent research has shown that there is a higher occurrence of cancer, such as breast, liver, and colon cancer, in patients with diabetes. Diabetes is characterized by altered metabolism; to understand how these alterations relate to increased cancer incidences, our lab investigated the molecular effects of a high glucose treatment in cancer cells, as this mimics the hyperglycemic conditions in diabetic patients. Previously our laboratory demonstrated that TAF1, a general transcription factor with intrinsic kinase activity, phosphorylates p53, a tumor suppressor and transcription factor known to protect the cell from DNA damage and maintain genomic integrity. Phosphorylation of p53 at Thr55 results in dissociation of p53 and TAF1 from promoters leading to transcription termination. Importantly, this regulation event contributes to cell cycle progression from G1 to S phase through dissociation from the p21 promoter. In addition, the lab has shown that TAF1 kinase activity is governed by cellular ATP concentrations, and may function as an ATP sensor in cells. Because TAF1 kinase is cellular ATP dependent, HG may increase tumorigenesis in vivo through Thr55-phosphorylation and inhibition of p53. This dissertation aims to provide additional evidence for the role TAF1 kinase and p53 regulation plays in a diabetic mouse model. My studies include creation of a T55A phosphorylation mutant through CRISPR/Cas9 genome editing, and the effects this mutation has on p53 regulation both in cell culture and in vivo. Further, I determine that our working model can be replicated in vivo, suggesting the importance of TAF1 kinase regulation and p53 inactivation in tumorigenesis. Additionally, I discover a new model for the role hyperglycemia plays in cell migration. Because the molecular mechanisms behind the link between diabetes and increased cancer risk are largely unknown, the discoveries shown here provide evidence that hyperglycemia can lead to cancer progression through multiple pathways