Twist1/Dnmt3a and miR186 establish a regulatory circuit that controls inflammation-associated prostate cancer progression.
Twist1/Dnmt3a and miR186 establish a regulatory circuit that controls inflammation-associated prostate cancer progression.
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Twist1/Dnmt3a 和 miR186 建立了一个控制炎症相关前列腺癌进展的调节回路。
DOI：
10.1038/oncsis.2017.16
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发表时间：
2017-04-10
期刊：
影响因子：
6.2
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Zhao X;Deng R;Wang Y;Zhang H;Dou J;Li L;Du Y;Chen R;Cheng J;Yu J
越来越多的证据表明，炎症微环境在前列腺癌（PCa）的进展中起着至关重要的作用，但其潜在机制尚不清楚。在这里，我们使用炎症相关的前列腺细胞转化模型筛选出一种关键的microRNA，miR 186，它在转化细胞中显著下调，并有效地挽救了转化的表型。在炎性细胞因子刺激下，活化的核因子κ B（NF-κB）/p65能够通过与非转化细胞中的miR 186启动子结合来诱导miR 186表达，而在转化细胞中该途径丧失。有趣的是，Twist 1是miR 186的下游靶点，其负责NF-κB/p65-miR 186通路的丧失。Twist 1通过一个新的负反馈环下调miR 186的表达，该环与E-box结合，同时募集Dnmt 3a，促进miR 186启动子的位点特异性CpG甲基化，从而阻断NF-κB/p65的转录活性和miR 186对炎症信号的反应性。高水平的Twist 1触发了这个反馈回路，该反馈回路是表观遗传开关的基础，这对于维持转化和晚期PCa状态至关重要。最后，我们的临床数据证实CpG甲基化和miR 186表达水平与炎症相关的人类PCa进展密切相关。
Increasing evidences suggest that inflammatory microenvironment has a crucial role in prostate cancer (PCa) progression; however, the underlying mechanisms are unclear. Here, we used the inflammation-associated prostate cellular transformation model to screen out a crucial microRNA, miR186, which was significantly downregulated in the transformed cells and effectively rescued the transformed phenotype. On stimulation of inflammatory cytokines, the activated nuclear factor kappa B (NF-κB)/p65 was able to induce miR186 expression through binding to its promoter in non-transformed cells, whereas this pathway was lost in transformed cells. Interestingly, Twist1, which is a reported downstream target of miR186, was responsible for the loss of NF-κB/p65-miR186 pathway. Twist1 downregulated miR186 expression in a novel negative feedback loop binding to the E-box and simultaneously recruiting Dnmt3a, which facilitated the site-specific CpG methylation of the miR186 promoter, thereby blocked the transcriptional activity of NF-κB/p65 and the responsiveness of miR186 to inflammatory signals. The high level of Twist1 triggered this feedback loop that underlies the epigenetic switch, which was essential for maintaining transformed and advanced PCa state. Finally, our clinical data confirmed that the CpG methylation and miR186 expression levels were closely related with inflammation-associated human PCa progression.
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影响因子：
3.7
作者：
Limame R;Wouters A;Pauwels B;Fransen E;Peeters M;Lardon F;De Wever O;Pauwels P
通讯作者：
Pauwels P
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作者：
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通讯作者：
Puisieux, Alain
影响因子：
4.1
作者：
Cao, YX;Jean, JC;Williams, MC
通讯作者：
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