Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis.
Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis.
复制标题
AGO2 的乙酰化通过增加致癌 miR-19b 的生物发生来促进癌症进展。
DOI：
10.1038/s41388-018-0530-7
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Zhang H;Wang Y;Dou J;Guo Y;He J;Li L;Liu X;Chen R;Deng R;Huang J;Xie R;Zhao X;Yu J
ArgAerte2(AGO2)是小RNA介导的基因沉默的效应器。越来越多的证据表明，AGO2的翻译后修饰可以在特定或全球水平上改变miRNA的活性。在miR-17-92编码的六个成熟miRNAs中，miR-19b1是最能发挥整个簇的致癌特性的。在这里，我们发现AGO2可以被P300/CBP乙酰化，可以被HDAC7去乙酰化，并且乙酰化发生在三个位点K720、K493和K355。在AGO2，K493R/K720R突变而不是K355R突变抑制miR-19b的生物发生。我们证明了AGO2的乙酰化特异性地增加了其招募前miR-19b1形成miPDC(miRNA前体沉积复合体)，从而促进miR-19b的成熟。Pre-miR-19b1末端环中的UGUGUG基序作为乙酰化AGO2识别和结合的特异性加工特征，对miRISC(miRNA诱导沉默复合体)负载复合体的组装至关重要。对公开的临床数据、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，AGO2乙酰化和miR-19b的高水平与肺癌患者的预后不良有关。我们的发现揭示了AGO2乙酰化在促进致癌miR-19b生物发生中的新功能，并提示AGO2乙酰化的调控具有潜在的临床意义。
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.