Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis.
Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis.
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DOI：
10.1158/0008-5472.can-17-0056
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发表时间：
2017-07-01
期刊：
影响因子：
11.2
通讯作者：
O'Hagan HM
中科院分区：
文献类型：
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作者：
Maiuri AR;Peng M;Podicheti R;Sriramkumar S;Kamplain CM;Rusch DB;DeStefano Shields CE;Sears CL;O'Hagan HM
DNA甲基化导致的基因异常沉默有助于癌症的发生，但这一过程是如何启动的仍不清楚。利用炎症诱导肿瘤发生的小鼠模型，我们检验了炎症促进表观遗传蛋白向染色质募集，启动肿瘤中的甲基化和基因沉默的假说。与正常上皮和非炎症诱导的肿瘤相比，炎症诱导的肿瘤在CpG岛上获得了DNA甲基化，其中一些与可能的肿瘤抑制基因相关。在肿瘤形成之前，高甲基化的基因表现出抑制染色质标记的丰富和表达的减少，这一时间点与炎症相关的DNA损伤的峰值水平一致。错配修复(MMR)蛋白MutS Homolog 2(MSH2)的丢失消除了在炎症诱导的肿瘤中观察到的早期炎症诱导的表观遗传学改变和DNA高甲基化改变。这些结果表明，炎症和MMR蛋白启动的早期表观遗传改变导致了肿瘤发生过程中的基因沉默，揭示了炎症驱动的癌症中表观遗传改变的新机制。了解这些机制将有助于药物疗法的发展，以减少癌症的发生。
Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared to normal epithelium and non-inflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis.