AGO2的乙酰化通过增加致癌的miR-19b生物发生来促进癌症进展。,Oncogene

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AGO2的乙酰化通过增加致癌的miR-19b生物发生来促进癌症进展。
Oncogene ( IF 6.9 ) Pub Date : 2018-Oct-10 , DOI: 10.1038/s41388-018-0530-7
Hailong Zhang , Yanli Wang , Jinzhuo Dou , Yanmin Guo , Jianfeng He , Lian Li , Xiaojia Liu , Ran Chen , Rong Deng , Jian Huang , Ruiyu Xie , Xian Zhao , Jianxiu Yu

Argonaute2（AGO2）是小RNA介导的基因沉默的效应子。越来越多的证据表明，AGO2的翻译后修饰可以在特定或整体水平上改变miRNA的活性。在由miR-17-92编码的六个成熟miRNA中，miR-19b1最有力发挥整个簇的致癌特性。在这里，我们确定AGO2可以被P300 / CBP乙酰化，并可以被HDAC7脱乙酰，并且乙酰化发生在三个位点K720，K493和K355。在AGO2处K493R / K720R而非K355R的突变会抑制miR-19b的生物发生。我们证明AGO2的乙酰化会特别增加其募集的前miR-19b1，以形成miPDC（miRNA前体沉积复合物），从而增强miR-19b的成熟度。在premiR-19b1的末端环中的主题UGUGUG，作为被乙酰化AGO2识别并结合的特定加工功能，对于组装miRISC（miRNA诱导的沉默复合物）加载复合物至关重要。对公共临床数据，异种移植小鼠模型以及肺癌组织的IHC和ISH染色的分析进一步证实，高水平的AGO2乙酰化和miR-19b均与肺癌患者的不良预后相关。我们的发现揭示了AGO2乙酰化在增加致癌miR-19b生物发生中的新功能，并表明AGO2乙酰化的调节具有潜在的临床意义。进一步证实，高水平的AGO2乙酰化和miR-19b与肺癌患者的不良预后相关。我们的发现揭示了AGO2乙酰化在增加致癌miR-19b生物发生中的新功能，并表明AGO2乙酰化的调节具有潜在的临床意义。进一步证实，高水平的AGO2乙酰化和miR-19b与肺癌患者的预后不良有关。我们的发现揭示了AGO2乙酰化在增加致癌miR-19b生物发生中的新功能，并表明AGO2乙酰化的调节具有潜在的临床意义。

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Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis.

Argonaute2 (AGO2) is an effector of small RNA mediated gene silencing. Increasing evidence show that post-translational modifications of AGO2 can change miRNA activity at specific or global levels. Among the six mature miRNAs that are encoded by miR-17-92, miR-19b1 is the most powerful to exert the oncogenic properties of the entire cluster. Here we identify that AGO2 can be acetylated by P300/CBP and deacetylated by HDAC7, and that acetylation occurs at three sites K720, K493, and K355. Mutation of K493R/K720R, but not K355R at AGO2, inhibits miR-19b biogenesis. We demonstrate that acetylation of AGO2 specifically increases its recruiting pre-miR-19b1 to form the miPDC (miRNA precursor deposit complex), thereby to enhance miR-19b maturation. The motif UGUGUG in the terminal-loop of pre-miR-19b1, as a specific processing feature that is recognized and bound by acetylated AGO2, is essential for the assembly of miRISC (miRNA-induced silencing complex) loading complex. Analyses on public clinical data, xenograft mouse models, and IHC and ISH staining of lung cancer tissues, further confirm that the high levels of both AGO2 acetylation and miR-19b correlate with poor prognosis in lung cancer patients. Our finding reveals a novel function of AGO2 acetylation in increasing oncogenic miR-19b biogenesis and suggests that modulation of AGO2 acetylation has potential clinical implications.

更新日期：2018-10-11

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