Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, 500 University Dr, Hershey, PA, 17033, USA.
Sci Rep. 2017 Aug 29;7(1):9711. doi: 10.1038/s41598-017-09859-x.
Nucleotide metabolism in cancer cells can influence malignant behavior and intrinsic resistance to therapy. Here we describe p53-dependent control of the rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) and its effect on pharmacokinetics of and response to 5-fluorouracil (5-FU). Using in silico/chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU treatment of cells. Consequently, decrease in Histone H3K9AC and increase in H3K27me3 marks at the DPYD promoter are observed concomitantly with reduced expression of DPYD mRNA and protein in a p53-dependent manner. Mechanistic studies reveal inhibition of DPYD expression by p53 is augmented following thymidylate synthase (TS) inhibition and DPYD repression by p53 is dependent on DNA-dependent protein kinase (DNA-PK) and Ataxia telangiectasia mutated (ATM) signaling. In-vivo, liver specific Tp53 loss increases the conversion of 5-FU to 5-FUH in plasma and elicits a diminished 5-FU therapeutic response in a syngeneic colorectal tumor model consistent with increased DPYD-activity. Our data suggest that p53 plays an important role in controlling pyrimidine catabolism through repression of DPYD expression, following metabolic stress imposed by nucleotide imbalance. These findings have implications for the toxicity and efficacy of the cancer therapeutic 5-FU.
癌细胞中的核苷酸代谢可以影响恶性行为和对治疗的内在耐药性。在这里，我们描述了 p53 对嘧啶分解代谢途径中限速酶二氢嘧啶脱氢酶（DPYD）的依赖性控制及其对 5-氟尿嘧啶（5-FU）药代动力学和反应的影响。通过计算机模拟/染色质免疫沉淀（ChIP）分析，我们在 DPYD 基因下游鉴定了一个保守的 p53 DNA 结合位点（p53BS），在细胞用 5-FU 处理后，p53 占据该位点的比例增加。因此，在 DPYD 启动子上同时观察到组蛋白 H3K9AC 减少和 H3K27me3 增加，伴随着 DPYD mRNA 和蛋白的表达减少，这是一种依赖于 p53 的方式。机制研究表明，p53 对 DPYD 表达的抑制作用在胸苷酸合成酶（TS）抑制后增强，并且 p53 对 DPYD 的抑制作用依赖于 DNA 依赖性蛋白激酶（DNA-PK）和共济失调毛细血管扩张突变（ATM）信号。在体内，肝特异性 Tp53 缺失增加了血浆中 5-FU 向 5-FUH 的转化，并在同基因结直肠肿瘤模型中引发了 5-FU 治疗反应的减弱，这与 DPYD 活性的增加一致。我们的数据表明，p53 通过抑制 DPYD 的表达，在核苷酸失衡引起的代谢应激后，在控制嘧啶分解代谢中发挥重要作用。这些发现对癌症治疗药物 5-FU 的毒性和疗效具有重要意义。
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