Abstract PR03: P53 inhibits the expression of the pyrimidine catabolic gene Dihydropyrimidine dehydrogenase (DPYD)

Fluorouracil (5-FU) a widely used chemotherapeutic drug whose unpredictable pharmacokinetics is controlled by the pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD), that has recently also been shown to be a gatekeeper of the epithelial-to-mesenchymal transition (EMT) in breast cancer. Relatively little is known about the transcriptional control of DPYD and here we show for the first time an interaction between p53 and DPYD (involved in catabolism of pyrimidines as well as 5-FU) where p53 represses both the base-line expression of DPYD and that following 5-FU administration in vitro and in vivo. This mechanism affects the catabolic conversion of 5-FU to 5-FUH2 in mice in vivo. Using an in-silico approach we also identified several putative p53 binding sites (P53DBS) in and around ~20Kb upstream and downstream of the mouse DPYD gene. In-vivo ChIP from mice livers identified a key p53DBS binding site downstream (chr3: 119451237-11941257) of the gene to which p53 binds to at about 1.8 ± 0.05 fold over untreated control following a single IV bolus of 5-FU (150 mg/kg bw). Interestingly DPYD mRNA and protein levels were decreased by 1.8 and 1.5 fold respectively (P< 0.0005) in a p53-dependent manner in the liver. Similarly DPYD-repression was documented at both the mRNA and protein levels in the wild-type (WT) p53-expressing cancer cell lines H460, HCT-116, and A569. To further characterize the functional effect of DPYD repression in vivo, we utilized mice w...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Cancer Metabolic Pathways: Oral Presentations - Proffered Abstracts Source Type: research