title: Identification of a novel E-box binding pyrrole-imidazole polyamide inhibiting MYC-driven cell proliferation.
abstract: The MYC transcription factor plays a crucial role in the regulation of cell cycle progression, apoptosis, angiogenesis, and cellular transformation. Due to its oncogenic activities and overexpression in a majority of human cancers, it is an interesting target for novel drug therapies. MYC binding to the E-box (5'-CACGTGT-3') sequence at gene promoters contributes to more than 4000 MYC-dependent transcripts. Owing to its importance in MYC regulation, we designed a novel sequence-specific DNA-binding pyrrole-imidazole (PI) polyamide, Myc-5, that recognizes the E-box consensus sequence. Bioinformatics analysis revealed that the Myc-5 binding sequence appeared in 5'- MYC binding E-box sequences at the eIF4G1, CCND1, and CDK4 gene promoters. Furthermore, ChIP coupled with detection by quantitative PCR indicated that Myc-5 has the ability to inhibit MYC binding at the target gene promoters and thus cause downregulation at the mRNA level and protein expression of its target genes in human Burkitt's lymphoma model cell line, P493.6, carrying an inducible MYC repression system and the K562 (human chronic myelogenous leukemia) cell line. Single i.v. injection of Myc-5 at 7.5 mg/kg dose caused significant tumor growth inhibition in a MYC-dependent tumor xenograft model without evidence of toxicity. We report here a compelling rationale for the identification of a PI polyamide that inhibits a part of E-box-mediated MYC downstream gene expression and is a model for showing that phenotype-associated MYC downstream gene targets consequently inhibit MYC-dependent tumor growth.
authors.affiliation: Division of Cancer Genetics, Department of Advanced Medical Science, Nihon University Research Institute of Medical Science, Tokyo, Japan; Department of Medicine, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mishra
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Makoto T
authors.initials: MT
authors.lastname: Kimura
authors.forename: Nobuko
authors.initials: N
authors.lastname: Koshikawa
authors.forename: Maki
authors.initials: M
authors.lastname: Ikeda
authors.forename: Shota
authors.initials: S
authors.lastname: Uekusa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawashima
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Igarashi
authors.forename: Diptiman
authors.initials: D
authors.lastname: Choudhury
authors.forename: Carla
authors.initials: C
authors.lastname: Grandori
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
authors.forename: Miki
authors.initials: M
authors.lastname: Ohira
authors.forename: Narendra K
authors.initials: NK
authors.lastname: Verma
authors.forename: Yujin
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Jin
authors.initials: J
authors.lastname: Takeuchi
authors.forename: Tsugumichi
authors.initials: T
authors.lastname: Koshinaga
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nemoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kusafuka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004268:DNA-Binding Proteins; D024721:E-Box Elements / Q000187:drug effects* / Q000235:genetics; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D051379:Mice; D016513:Mice, SCID; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics; D011758:Pyrroles / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: C530104:CCND1 protein, human; D004268:DNA-Binding Proteins; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D007093:Imidazoles; C489427:MYC protein, human; D009757:Nylons; D016271:Proto-Oncogene Proteins c-myc; D011758:Pyrroles; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4
keywords: Cell cycle; E-Box; MYC; pyrrole-imidazole polyamide; transcription therapy