Targeted Suppression of EVI1 Oncogene Expression by Sequence-Specific Pyrrole-Imidazole Polyamide
Targeted Suppression of EVI1 Oncogene Expression by Sequence-Specific Pyrrole-Imidazole Polyamide
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DOI：
10.1016/j.chembiol.2014.07.019
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发表时间：
2014-10-23
影响因子：
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通讯作者：
Sugiyama, Hiroshi
中科院分区：
文献类型：
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作者：
Syed, Junetha;Pandian, Ganesh N.;Sugiyama, Hiroshi
人类异位病毒整合位点1(EVI1)是一种癌基因转录因子，在多种侵袭性癌症中起关键作用。它的选择性调节被认为改变了癌症特异性基因调控网络。吡咯咪唑聚酰胺(PIP)是一类小分子DNA结合剂，可以针对任何特定的DNA序列进行设计。在这里，我们报道了一种序列特异性的吡咯咪唑聚酰胺，PIP1，它可以靶向EVI1最小启动子中REL/ELK1结合位点的特定碱基对。设计的PIP1能显著抑制MDA-MB-231细胞中的EVI1。全转录组分析证实，PIP1影响了EVI1介导的基因调控的一部分。体外实验表明，这种聚酰胺还可以有效地抑制乳腺癌细胞的迁移。综上所述，这些结果表明，EVI1靶向的PIP1是癌细胞中有效的转录调节因子。
Human ectopic viral integration site 1 (EVI1) is an oncogenic transcription factor known to play a critical role in many aggressive forms of cancer. Its selective modulation is thought to alter the cancer-specific gene regulatory networks. Pyrrole-imidazole polyamides (PIPs) are a class of small DNA binders that can be designed to target any destined DNA sequence. Herein, we report a sequence-specific pyrrole-imidazole polyamide, PIP1, which can target specific base pairs of the REL/ELK1 binding site in the EVI1 minimal promoter. The designed PIP1 significantly inhibited EVI1 in MDA-MB-231 cells. Whole-transcriptome analysis confirmed that PIP1 affected a fraction of EVI1-mediated gene regulation. In vitro assays suggested that this polyamide can also effectively inhibit breast cancer cell migration. Taken together, these results suggest that EVI1-targeted PIP1 is an effective transcriptional regulator in cancer cells.