p53 β-hydroxybutyrylation attenuates p53 activity
p53 β-hydroxybutyrylation attenuates p53 activity
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p53的β-羟基丁酰化会减弱p53的活性
DOI：
10.1038/s41419-019-1463-y
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发表时间：
2019-03-11
影响因子：
9
通讯作者：
Zhao, Wenhui
中科院分区：
文献类型：
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作者：
Liu, Kun;Li, Fangzhou;Zhao, Wenhui
p53是一种重要的肿瘤抑制因子，其活性通过翻译后修饰进行微调。已有研究报道β-羟基丁酸酯（BHB）诱导的β-羟基丁酰化（Kbhb）是一种新的组蛋白翻译后修饰。在这里，我们报告说，p53被kbhb修饰，这种修饰发生在p53的赖氨酸120，319和370。我们证明，在培养的细胞与BHB处理和禁食小鼠的胸腺组织中，p53 kbhb的水平显着增加，CBP催化p53 kbhb。我们表明，p53 kbhb导致p53乙酰化水平降低，p53下游基因p21和PUMA的表达减少，以及在p53激活条件下培养细胞中细胞生长停滞和细胞凋亡减少。在饥饿条件下的小鼠胸腺组织中观察到类似的结果，这导致血清BHB浓度增加，并对由以下引起的遗传毒性应激作出反应：照射以激活p53。因此，我们的研究结果表明，BHB介导的p53 kbhb是p53活性调节的一种新机制，这可能解释酮体与肿瘤之间的联系，并可能为癌症治疗提供有希望的治疗靶点。
p53 is an essential tumor suppressor, whose activity is finely tuned by the posttranslational modifications. Previous research has reported that beta-hydroxybutyrate (BHB) induces beta-hydroxybutyrylation (Kbhb), which is a novel histone posttranslational modification. Here we report that p53 is modified by kbhb and that this modification occurs at lysines 120, 319, and 370 of p53. We demonstrate that the level of p53 kbhb is dramatically increased in cultured cells treated with BHB and in thymus tissues of fasted mice, and that CBP catalyze p53 kbhb. We show that p53 kbhb results in lower levels of p53 acetylation and reduced expression of the p53 downstream genes p21 and PUMA, as well as reduced cell growth arrest and apoptosis in cultured cells under p53-activating conditions. Similar results were observed in mouse thymus tissue under starvation conditions, which result in increased concentrations of serum BHB, and in response to genotoxic stress caused by.-irradiation to activate p53. Our findings thus show that BHB-mediated p53 kbhb is a novel mechanism of p53 activity regulation, which may explain the link between ketone bodies and tumor, and which may provide promising therapeutic target for cancer treatment.