美国纪念斯隆凯特琳癌症研究中心Lydia W. S. Finley和Scott W. Lowe研究组，合作揭示了α-酮戊二酸与p53蛋白在肿瘤抑制过程中调控细胞命运。2019年9月18日，《自然》在线发表了相关论文。
研究人员发现p53重塑癌细胞代谢，以加强染色质和基因表达的变化，从而有利于癌前细胞的命运。在源自胰腺导管腺癌（PDAC）的KRAS突变小鼠模型的癌细胞中恢复p53功能导致α-酮戊二酸（αKG，也称为2-氧代戊二酸）的积累，该代谢物也作为一类染色质修饰酶的专用底物。p53诱导转录程序，其是癌前分化的特征，并且这种作用可以通过添加细胞可渗透的αKG而部分模拟。增加的αKG依赖性染色质修饰水平5-羟甲基胞嘧啶（5hmC）伴随着由p53触发的肿瘤细胞分化，而5hmC的减少表征了从恶化前病变到去分化的恶性病变的转变，其与Trp53的突变相关。
通过抑制氧代戊二酸脱氢酶（三羧酸循环的酶）来强制p53缺陷型PDAC细胞中αKG的积累，即特异性地导致5hmC增加、肿瘤细胞分化和肿瘤细胞适应性降低。相反，增加琥珀酸的细胞内水平（αKG依赖性双加氧酶的竞争性抑制剂）会减弱p53驱动的肿瘤抑制。这些数据表明αKG是p53介导的肿瘤抑制的效应物，并且αKG在p53缺陷肿瘤中的积累可以驱动肿瘤细胞分化并拮抗恶性进展。
据了解，肿瘤抑制因子TP53基因在大多数人类癌症以及超过70％的PDAC中发生突变。野生型p53在细胞应激反应中积累，并调节基因表达以改变细胞命运并防止肿瘤进展。野生型p53调节细胞代谢途径已经知道，但限制癌症进展的p53依赖性代谢改变仍然知之甚少。
附：英文原文
Title: α-Ketoglutarate links p53 to cell fate during tumour suppression
Author: John P. Morris IV, Jossie J. Yashinskie, Richard Koche, Rohit Chandwani, Sha Tian, Chi-Chao Chen, Timour Baslan, Zoran S. Marinkovic, Francisco J. Sánchez-Rivera, Steven D. Leach, Carlos Carmona-Fontaine, Craig B. Thompson, Lydia W. S. Finley & Scott W. Lowe
Issue&Volume: 18 September 2019
Abstract:
The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development2. Wild-type p53 is also known to modulate cellular metabolic pathways3, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of α-ketoglutarate (αKG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable αKG. Increased levels of the αKG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of αKG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase—an enzyme of the tricarboxylic acid cycle—specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of αKG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that αKG is an effector of p53-mediated tumour suppression, and that the accumulation of αKG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.
DOI: 10.1038/s41586-019-1577-5
Source:https://www.nature.com/articles/s41586-019-1577-5
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
