由关键代谢物耗竭引起的表观遗传重编程是一种进化上古老的肿瘤发生途径。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-16 DOI:10.1242/dmm.052313
Zhe Chen, Xiaomeng Zhang, Mingxi Deng, Chongyang Li, Thi Thuy Nguyen, Min Liu, Kun Dou, Toyotaka Ishibashi, Jiguang Wang, Yan Yan
{"title":"由关键代谢物耗竭引起的表观遗传重编程是一种进化上古老的肿瘤发生途径。","authors":"Zhe Chen, Xiaomeng Zhang, Mingxi Deng, Chongyang Li, Thi Thuy Nguyen, Min Liu, Kun Dou, Toyotaka Ishibashi, Jiguang Wang, Yan Yan","doi":"10.1242/dmm.052313","DOIUrl":null,"url":null,"abstract":"<p><p>Tumor growth is a challenge for multicellular life forms. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities. In a fly tumor model caused by loss of cell polarity genes, we identified two key metabolic changes: first, systemic depletion of acetyl-CoA leading to a reduction in histone acetylation levels and stochastic silencing of actively transcribed genes; and second, defects in the methionine cycle causing systemic depletion of S-adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process inhibits tumor growth. To understand the evolutionary origin of tumorigenesis, we performed comparative studies of fly and human tumors and found that human tumors with metabolic signatures similar to those of fly tumors have a lower mutational load, younger patient age and lower DNA methylation levels. This study indicates that depletion of key metabolites is an evolutionarily ancient driving force for tumorigenesis.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 6","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208194/pdf/","citationCount":"0","resultStr":"{\"title\":\"Epigenetic reprogramming induced by key metabolite depletion is an evolutionarily ancient path to tumorigenesis.\",\"authors\":\"Zhe Chen, Xiaomeng Zhang, Mingxi Deng, Chongyang Li, Thi Thuy Nguyen, Min Liu, Kun Dou, Toyotaka Ishibashi, Jiguang Wang, Yan Yan\",\"doi\":\"10.1242/dmm.052313\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Tumor growth is a challenge for multicellular life forms. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities. In a fly tumor model caused by loss of cell polarity genes, we identified two key metabolic changes: first, systemic depletion of acetyl-CoA leading to a reduction in histone acetylation levels and stochastic silencing of actively transcribed genes; and second, defects in the methionine cycle causing systemic depletion of S-adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process inhibits tumor growth. To understand the evolutionary origin of tumorigenesis, we performed comparative studies of fly and human tumors and found that human tumors with metabolic signatures similar to those of fly tumors have a lower mutational load, younger patient age and lower DNA methylation levels. This study indicates that depletion of key metabolites is an evolutionarily ancient driving force for tumorigenesis.</p>\",\"PeriodicalId\":11144,\"journal\":{\"name\":\"Disease Models & Mechanisms\",\"volume\":\"18 6\",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208194/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Disease Models & Mechanisms\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1242/dmm.052313\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/16 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Disease Models & Mechanisms","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1242/dmm.052313","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/16 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

肿瘤的生长是对多细胞生命形式的挑战。与需要数年才能形成的人类肿瘤相反,短寿命物种的肿瘤可以在几天内产生,而不会积累多次突变,这就提出了不同物种的肿瘤发生途径是否有任何共性的问题。在由细胞极性基因缺失引起的果蝇肿瘤模型中,我们发现了两个关键的代谢变化:首先,乙酰辅酶a的系统性消耗导致组蛋白乙酰化水平降低和活性转录基因的随机沉默;其次,蛋氨酸循环中的缺陷导致s -腺苷型蛋氨酸的系统性耗散,进一步降低组蛋白甲基化水平,导致转座子的随机激活。蛋氨酸代谢过程的扰动抑制肿瘤生长。为了了解肿瘤发生的进化起源,我们对苍蝇和人类肿瘤进行了比较研究,发现具有与苍蝇肿瘤相似代谢特征的人类肿瘤具有更低的突变负荷、更年轻的患者年龄和更低的DNA甲基化水平。这项研究表明,关键代谢物的消耗是一种进化上古老的肿瘤发生驱动力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Epigenetic reprogramming induced by key metabolite depletion is an evolutionarily ancient path to tumorigenesis.

Tumor growth is a challenge for multicellular life forms. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities. In a fly tumor model caused by loss of cell polarity genes, we identified two key metabolic changes: first, systemic depletion of acetyl-CoA leading to a reduction in histone acetylation levels and stochastic silencing of actively transcribed genes; and second, defects in the methionine cycle causing systemic depletion of S-adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process inhibits tumor growth. To understand the evolutionary origin of tumorigenesis, we performed comparative studies of fly and human tumors and found that human tumors with metabolic signatures similar to those of fly tumors have a lower mutational load, younger patient age and lower DNA methylation levels. This study indicates that depletion of key metabolites is an evolutionarily ancient driving force for tumorigenesis.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信