MicroRNAs miR-199a-5p and-3p Target the Brm Subunit of SWI/SNF to Generate a Double-Negative Feedback Loop in a Variety of Human Cancers
MicroRNAs miR-199a-5p and-3p Target the Brm Subunit of SWI/SNF to Generate a Double-Negative Feedback Loop in a Variety of Human Cancers
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DOI：
10.1158/0008-5472.can-10-2345
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Iba, Hideo
中科院分区：
文献类型：
--
作者：
Sakurai, Kouhei;Furukawa, Chihiro;Iba, Hideo
染色质重塑复合物SWI/SNF是一种重要的表观遗传调节因子，包括一个Brm或BRG 1分子作为催化亚基。Brm和BRG 1的功能并不相同，因此这种复合物可以正向或负向调节基因表达，这取决于它被募集到的启动子。值得注意的是，由于转录后抑制而导致的Brm衰减经常发生在人类肿瘤细胞中，其中该事件有助于其致癌潜力。在这里，我们报告说，Brm mRNA的3 '-非翻译区有两个位点，有效地由microRNA miR-199 a-5 p和-3p靶向，揭示了一种新的机制，调节Brm型SWI/SNF活性。对miR-199 a-2（miPPR-199 a-2）的推定启动子区域的计算作图已将其定义为这些肿瘤细胞系中miR-199 a-5 p和-3p产生的主要贡献基因座。我们通过直接启动子分析验证了该预测区域，以证实Egr 1是miR-199 a-2基因的强正调控因子。重要的是，我们还发现Egr 1，miR-199 a-5 p和miR-199 a-3 p在Brm缺陷肿瘤细胞系中以高水平表达，但在Brm表达肿瘤细胞中仅少量表达。最后，我们还获得了Brm负调控Egr 1的证据。总之，我们的研究结果表明，miR-199 a和Brm通过Egr 1形成了一个双负反馈回路，导致在癌变过程中产生这两种不同的细胞类型。这一机制可以部分解释为什么miR-199 a-5 p和-3p在多种肿瘤中被报道上调或下调。Cancer Res; 71（5）; 1680-9.（C）2010年AACR。
The chromatin remodeling complex SWI/SNF is an important epigenetic regulator that includes one Brm or BRG1 molecule as catalytic subunit. Brm and BRG1 do not function identically, so this complex can regulate gene expression either positively or negatively, depending on the promoter to which it is recruited. Notably, Brm attenuation due to posttranscription suppression occurs often in human tumor cells, in which this event contributes to their oncogenic potential. Here, we report that the 3'-untranslated region of Brm mRNA has two sites that are efficiently targeted by the microRNAs miR-199a-5p and -3p, revealing a novel mechanism for modulation of Brm-type SWI/SNF activity. Computational mapping of the putative promoter region of miR-199a-2 (miPPR-199a-2) has defined it as the major contributing genetic locus for miR-199a-5p and-3p production in these tumor cell lines. We validated this predicted region by direct promoter analysis to confirm that Egr1 is a strong positive regulator of the miR-199a-2 gene. Importantly, we also showed that Egr1, miR-199a-5p, and miR-199a-3p are expressed at high levels in Brm-deficient tumor cell lines but only marginally in Brm-expressing tumor cells. Finally, we also obtained evidence that Brm negatively regulates Egr1. Together, our results reveal that miR-199a and Brm form a double-negative feedback loop through Egr1, leading to the generation of these two distinct cell types during carcinogenesis. This mechanism may offer a partial explanation for why miR-199a-5p and -3p have been reported to be either upregulated or down-regulated in a variety of tumors. Cancer Res; 71(5); 1680-9. (C)2010 AACR.