The Role of High Glucose in Tumorigenesis Using Genome Wide Analysis

Altered cellular metabolism is considered a crucial hallmark of cancer, and has been an area of accelerated research. Interestingly, metabolic alterations in cancer can lead to changes in metabolite concentration, and these may play a role in tumorigenesis through functions that are not overtly metabolic. Tumor suppressor p53 plays a prominent role in cancer and much of human biology. Many functions have been attributed to p53, including roles in DNA repair and recombination through association with proteins involved in genome stability and chromatin modification. However, its broadest cellular effect is through its function as a transcription factor (TF). p53 is regulated through multiple post-translational modifications (PTMs) in response to a variety of cellular stresses including DNA damage. One important PTM is phosphorylation on the Thr55 residue, which is mediated by TBP Associated Factor 1 (TAF1) on the p21 promoter and leads to p53 promoter dissociation and termination of p21 transcription. TAF1 is the largest subunit of transcription factor TFIID and a cell cycle regulatory protein important for G1 phase progression. Interestingly, TAF1 phosphorylates p53 in a cellular ATP level-dependent manner. Because high glucose (HG) conditions lead to increased cellular ATP levels, we tested its effect on p53 function and found that global p53 binding to target promoters is reduced under HG conditions even in the presence of DNA damage. Functional analysis of cell growth inhibition as well as cell apoptosis suggests HG is a potent inhibitor of these p53-dependent cellular responses. Further, we examined the overall HG effect on the DNA damage-dependent gene expression changes and found that HG alters the DNA damage transcriptome. Importantly, HG affected the expression of genes that have already been shown to play a role in cancer. These studies suggest that cancer cells use the dynamic nature of cell metabolism to promote transformation via metabolite concentration. Altogether, this work establishes a molecular mechanism by which hyperglycemia may indirectly contribute to malignant transformation, providing an explanation for the association between diabetes and cancer