FASN, the sole cytosolic enzyme responsible for de novo palmitate synthesis in mammalian cells, has been associated with poor prognosis in cancer and shown to cause drug and radiation resistance by upregulating DNA damage repair via suppression of p65 expression. Targeting FASN by repurposing proton pump inhibitors has generated impressive outcomes in triple-negative breast cancer patients. While p65 regulation of DNA damage repair was thought to be due to its suppression of poly(ADP-ribose) polymerase 1 gene transcription, the mechanism of FASN regulation of p65 expression was unknown. In this study, we show that FASN regulates p65 stability by controlling its phosphorylation at Thr, which recruits the peptidyl-prolyl isomerase Pin1 that is known to stabilize many proteins in the nucleus. This regulation is mediated by palmitate, the FASN catalytic product, not by FASN protein per se. This finding of FASN regulation of p65 stability via phosphorylation of Thr and isomerization by Pin1 implicates that FASN and its catalytic product palmitate may play an important role in regulating protein stability in general and p65 more specifically.

中文翻译：

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FASN 通过 Thr254 磷酸化和 Pin1 异构化降低 p65 的稳定性，从而负调节 p65 表达

FASN 是哺乳动物细胞中负责从头合成棕榈酸酯的唯一胞质酶，与癌症预后不良有关，并且通过抑制 p65 表达来上调 DNA 损伤修复，从而导致药物和放射耐药性。通过重新利用质子泵抑制剂来靶向 FASN，在三阴性乳腺癌患者中产生了令人印象深刻的结果。虽然 p65 对 DNA 损伤修复的调节被认为是由于其抑制聚（ADP-核糖）聚合酶 1 基因转录，但 FASN 对 p65 表达的调节机制尚不清楚。在这项研究中，我们证明 FASN 通过控制 Thr 的磷酸化来调节 p65 的稳定性，Thr 会招募肽酰脯氨酰异构酶 Pin1，已知该酶可以稳定细胞核中的许多蛋白质。这种调节是由 FASN 催化产物棕榈酸酯介导的，而不是由 FASN 蛋白本身介导。 FASN 通过 Thr 磷酸化和 Pin1 异构化来调节 p65 稳定性的这一发现表明 FASN 及其催化产物棕榈酸酯可能在调节蛋白质稳定性（更具体地说是 p65）中发挥重要作用。