Syed Junetha, Pandian Ganesh N, Sato Shinsuke, Taniguchi Junichi, Chandran Anandhakumar, Hashiya Kaori, Bando Toshikazu, Sugiyama Hiroshi
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Chem Biol. 2014 Oct 23;21(10):1370-1380. doi: 10.1016/j.chembiol.2014.07.019. Epub 2014 Sep 11.
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.
人类异位病毒整合位点1（EVI1）是一种致癌转录因子，已知在许多侵袭性癌症形式中起关键作用。其选择性调节被认为会改变癌症特异性基因调控网络。吡咯-咪唑聚酰胺（PIPs）是一类小型DNA结合剂，可设计用于靶向任何指定的DNA序列。在此，我们报告了一种序列特异性吡咯-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在MDA-MB-231细胞中显著抑制EVI1。全转录组分析证实PIP1影响了一部分EVI1介导的基因调控。体外试验表明，这种聚酰胺还可以有效抑制乳腺癌细胞迁移。综上所述，这些结果表明靶向EVI1的PIP1是癌细胞中一种有效的转录调节因子。
