Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells
Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells
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DOI：
10.1016/j.bbrc.2008.12.098
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发表时间：
2009-02-13
影响因子：
3.1
通讯作者：
Liang, Gangning
中科院分区：
文献类型：
--
作者：
Saito, Yoshimasa;Friedman, Jeffrey M.;Liang, Gangning
研究表明，miRNAs的异常表达参与了癌症的发生和发展，并且一些miRNAs已被表征为肿瘤抑制因子或癌基因。通过表观遗传疗法恢复肿瘤抑制基因的表达在癌症治疗中具有巨大的潜力，并且已经显示一些miRNA可以通过癌细胞中的表观遗传改变从其自身的启动子直接调节。然而，大多数miRNA位于转录单位的内含子区域内，并且尚不清楚内含子miRNA是否也可以被表观遗传学调控。在这里，我们表明，肿瘤抑制miR-126，这是位于EGFL 7基因的内含子，在癌细胞系和原发性膀胱和前列腺肿瘤下调。成熟的miR-126可以由EGFL 7的三种不同转录物产生，每种转录物都有自己的启动子。有趣的是，miR-126和具有CpG岛启动子的EGFL 7的转录物之一在癌细胞系中通过DNA甲基化和组蛋白脱乙酰化的抑制剂同时上调。这些发现表明，表观遗传变化可以通过直接控制其宿主基因来控制肿瘤抑制内含子miRNA的表达。因此，表观遗传疗法不仅直接激活来自其自身启动子的miRNA，而且还激活内含子miRNA及其宿主基因。这揭示了表观遗传疗法的额外机制和抗癌作用。(C)2008年爱思唯尔公司All rights reserved.
Studies have shown that aberrant expression of miRNAs is involved in the initiation and progression of cancer, and several miRNAs have been characterized as tumor suppressors or oncogenes. Restoring the expression Of tumor suppressor genes by epigenetic therapy has great potential in cancer treatment and it has been shown that some miRNAs can be directly regulated from their own promoters by epigenetic alterations in cancer cells. However, the majority of miRNAs are located within intronic regions of transcription units and it was unclear if intronic miRNAs can also be epigenetically regulated. Here we show that the tumor Suppressor miR-126, which is located within an intron of the EGFL7 gene, is down-regulated in cancer cell lines and in primary bladder and prostate tumors. Mature miR-126 can be generated from three different transcripts of EGFL7 with each one having its own promoter. Interestingly, miR-126 and one of the transcripts of EGFL7 that has a CpG island promoter are concomitantly upregulated in cancer cell lines by inhibitors of DNA methylation and histone deacetylation. These findings suggest that epigenetic changes can control the expression of tumor suppressor intronic miRNAs by directly controlling their host genes. Thus, epigenetic therapy not only directly activates miRNAs from their own promoters, but also activates intronic miRNAs together with their host genes. This reveals an additional mechanism and anticancer effect of epigenetic therapy. (C) 2008 Elsevier Inc. All rights reserved.