The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid β-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.

p53 作为有效肿瘤抑制因子发挥作用的代谢途径尚不完全清楚。在这里，我们报告说，通过与维生素 D 受体 (VDR) 结合，p53 诱导了许多编码过氧化物酶体脂肪酸 β-氧化 (FAO) 酶的基因。这导致细胞溶质乙酰辅酶 A 水平升高和酶 5-氨基咪唑-4-甲酰胺核糖核苷酸甲酰转移酶/IMP 环化水解酶 (ATIC) 的乙酰化，后者催化嘌呤生物合成途径的最后两个步骤。这个由赖氨酸乙酰转移酶 2B (KAT2B) 介导的乙酰化步骤发生在 ATIC Lys 266，显着抑制 ATIC 活性，并与体外和体内结直肠癌 (CRC) 肿瘤生长呈负相关，ATIC 的乙酰化在人类 CRC 中下调样品。具有高水平 ATIC 的 p53 缺陷型 CRC 更容易受到 ATIC 抑制。总的来说，这些发现将 p53 与过氧化物酶体 FAO、嘌呤生物合成和 CRC 发病机制联系起来，其方式受 ATIC 乙酰化水平的调节。