title: Targeted suppression of EVI1 oncogene expression by sequence-specific pyrrole-imidazole polyamide.
abstract: 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.
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Junetha
authors.initials: J
authors.lastname: Syed
authors.affiliation: Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Sakyo, Kyoto 606-8501, Japan.
authors.forename: Ganesh N
authors.initials: GN
authors.lastname: Pandian
authors.affiliation: Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Sakyo, Kyoto 606-8501, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Taniguchi
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Anandhakumar
authors.initials: A
authors.lastname: Chandran
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Hashiya
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.affiliation: 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. Electronic address: hs@kuchem.kyoto-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000074008:MDS1 and EVI1 Complex Locus Protein; D009757:Nylons / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011401:Promoter Regions, Genetic; D020569:Proto-Oncogene Proteins c-rel / Q000737:chemistry / Q000378:metabolism; D011519:Proto-Oncogenes / Q000235:genetics; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D007093:Imidazoles; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D009757:Nylons; D010455:Peptides; D020569:Proto-Oncogene Proteins c-rel; D011758:Pyrroles; D012333:RNA, Messenger; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C029899:imidazole