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Identification of a novel E‐box binding pyrrole‐imidazole polyamide inhibiting MYC ‐driven cell proliferation
Author(s) -
Mishra Rajeev,
Watanabe Takayoshi,
Kimura Makoto T.,
Koshikawa Nobuko,
Ikeda Maki,
Uekusa Shota,
Kawashima Hiroyuki,
Wang Xiaofei,
Igarashi Jun,
Choudhury Diptiman,
Grandori Carla,
Kemp Christopher J.,
Ohira Miki,
Verma Narendra K.,
Kobayashi Yujin,
Takeuchi Jin,
Koshinaga Tsugumichi,
Nemoto Norimichi,
Fukuda Noboru,
Soma Masayoshi,
Kusafuka Takeshi,
Fujiwara Kyoko,
Nagase Hiroki
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12610
Subject(s) - promoter , biology , microbiology and biotechnology , cancer research , k562 cells , gene expression , gene , biochemistry
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 eIF 4G1, CCND 1, and CDK 4 gene promoters. Furthermore, Ch IP 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.

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