Inflammation-induced DNA methylation of DNA polymerase gamma alters the metabolic profile of colon tumors.
Inflammation-induced DNA methylation of DNA polymerase gamma alters the metabolic profile of colon tumors.
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DOI：
10.1186/s40170-018-0182-7
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发表时间：
2018
影响因子：
5.9
通讯作者：
O'Hagan HM
中科院分区：
文献类型：
--
作者：
Maiuri AR;Li H;Stein BD;Tennessen JM;O'Hagan HM
炎症、新陈代谢和表观遗传调节是高度相互关联的过程，可以在肿瘤发生过程中改变。然而，由于这些相互作用的复杂性，很难证明肿瘤发生过程中的直接因果关系。此前，利用炎症诱导的小鼠结肠肿瘤发生模型，我们确定在炎症诱导的肿瘤中，DNA聚合酶γ催化亚单位(Polg)的启动子是DNA高甲基化和沉默的，但在非炎症诱导的(Mock)肿瘤中不是，这表明炎症可以通过促进肿瘤形成过程中的DNA甲基化来诱导Polg的沉默。Polg是唯一的线粒体DNA聚合酶，Polg的突变会导致人类线粒体疾病。由于线粒体在代谢中的作用，我们假设，与模拟肿瘤相比，在炎症诱导的肿瘤中，Polg的沉默将导致这些肿瘤的代谢发生改变。从炎症诱导的结肠肿瘤形成的小鼠模型中检测了炎症诱导的和模拟的结肠肿瘤和结肠上皮细胞Polg的表达、线粒体和代谢的变化。从这些组织中提取的有机化合物用于研究Polg缺失对线粒体和代谢的直接影响。我们证明，与正常上皮或模拟肿瘤相比，Polg表达降低的炎症诱导肿瘤的线粒体DNA含量和线粒体数量都减少了。来自模拟肿瘤和炎症诱导肿瘤的肿瘤样物质保留了原始肿瘤的主要特征。与模拟肿瘤相比，炎症诱导的类肿瘤增加了葡萄糖的摄取和乳酸的分泌。ShRNA介导的Polg在模拟肿瘤中的敲除降低了mtDNA含量，增加了葡萄糖摄取和乳酸分泌，并使肿瘤对氧化应激更具抵抗力。这些结果表明，炎症诱导的DNA甲基化和Polg的沉默通过导致线粒体水平降低和代谢改变在肿瘤发生过程中发挥重要作用。加强对新陈代谢如何改变和驱动炎症诱导的肿瘤形成的理解将提供潜在的治疗靶点。本文的在线版本(10.1186/s40170180182-7)包含向授权用户提供的补充材料。
Inflammation, metabolism, and epigenetic modulation are highly interconnected processes that can be altered during tumorigenesis. However, because of the complexity of these interactions, direct cause and effect during tumorigenesis have been difficult to prove. Previously, using a murine model of inflammation-induced colon tumorigenesis, we determined that the promoter of the catalytic subunit of DNA polymerase gamma (Polg) is DNA hypermethylated and silenced in inflammation-induced tumors, but not in non-inflammation-induced (mock) tumors, suggesting that inflammation can induce silencing of Polg through promoting DNA methylation during tumorigenesis. Polg is the only mitochondrial DNA polymerase and mutations in Polg cause mitochondrial diseases in humans. Because of the role of mitochondria in metabolism, we hypothesized that silencing of Polg in inflammation-induced tumors would result in these tumors having altered metabolism in comparison to mock tumors. Inflammation-induced and mock colon tumors and colon epithelium from a mouse model of inflammation-induced colon tumorigenesis were assayed for alterations in Polg expression, mitochondria, and metabolism. Organoids derived from these tissues were used to study the direct effect of loss of Polg on mitochondria and metabolism. We demonstrate that inflammation-induced tumors with reduced Polg expression have decreased mitochondrial DNA content and numbers of mitochondria compared to normal epithelium or mock tumors. Tumoroids derived from mock and inflammation-induced tumors retained key characteristics of the original tumors. Inflammation-induced tumoroids had increased glucose uptake and lactate secretion relative to mock tumoroids. shRNA-mediated knockdown of Polg in mock tumoroids reduced mtDNA content, increased glucose uptake and lactate secretion, and made the tumoroids more resistant to oxidative stress. These results suggest that inflammation-induced DNA methylation and silencing of Polg plays an important role in the tumorigenesis process by resulting in reduced mitochondria levels and altered metabolism. An enhanced understanding of how metabolism is altered in and drives inflammation-induced tumorigenesis will provide potential therapeutic targets. The online version of this article (10.1186/s40170-018-0182-7) contains supplementary material, which is available to authorized users.
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影响因子：
3.5
作者：
Hance, N;Ekstrand, MI;Trifunovic, A
通讯作者：
Trifunovic, A
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3.8
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