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Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86599 | GEO | 2016/11/01

SECONDARY ACCESSION(S): PRJNA342329

REPOSITORIES: GEO

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Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes (SW480)

Project description:Pyrrole-imidazole polyamides are versatile DNA minor groove binders and attractive therapeutic options against oncological targets, especially upon functionalization with an alkylating agent such as endo-seco-CBI. These molecules also provide an alternative for oncogenes deemed “undruggable” at the protein level, where the absence of solvent-accessible pockets or structural crevices prevent the formation of protein-inhibitor ligands; nevertheless, the genome-wide effect of pyrrole-imidazole polyamide binding remain largely unclear to-date. Here we propose a next-generation sequencing-based workflow combined with whole genome expression arrays to address such issue using a candidate anti-cancer alkylating agent, KR12, against codon 12 mutant KRAS. Biotinylating KR12 enables the means to identify its genome-wide effects in living cells and possible biological implications via a coupled workflow of enrichment-based sequencing and expression microarrays. The subsequent computational pathway and expression analyses allow the identification of its genomic binding sites, as well as a route to explore a polyamide’s possible genome-wide effects. Among the 3,343 KR12 binding sites identified in the human LS180 colorectal cancer genome, the reduction of KR12-bound gene expressions was also observed. Additionally, the coupled microarray-sequencing analysis also revealed some insights about the effect of local chromatin structure on pyrrole-imidazole polyamide, which had not been fully understood to-date. A comparative analysis with KR12 in a different human colorectal cancer genome SW480 also showed agreeable agreements of KR12 binding affecting gene expressions. Combination of these analyses thus suggested the possibility of applying this approach to other pyrrole-imidazole polyamides to reveal further biological details about the effect of polyamide binding in a genome.

2016-11-01 | GSE86598 | GEO

Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes (LS180)

2016-11-01 | GSE86597 | GEO

Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes

Project description:Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes

| PRJNA342329 | ENA

Direct Targeting of MYCN Gene Amplification by Alkylating Pyrrole-Imidazole Polyamide and CRISPR/Cas9 in Neuroblastoma Cells (CHP-134)

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-12-25 | GSE121530 | GEO

Identification of Binding Targets of a Pyrrole-Imidazole Polyamide KR12 in the LS180 Colorectal Cancer Genome.

Project description: Not available

| S-EPMC5087912 | biostudies-literature

Antitumor activity of a pyrrole-imidazole polyamide

Project description:We report that a DNA minor groove binding hairpin pyrrole-imidazole (Py-Im) polyamide interferes with RNA polymerase II (RNAP2) activity in cell culture. Genome-wide mapping of RNAP2 binding shows reduction of occupancy preferentially at transcription start sites (TSS), while occupancy at enhancer sites are is unchanged. Genome-wide mapping of RNA polymerase II in LNCaP cells treated with DHT and DHT with Py-Im polyamide.

2013-01-31 | E-GEOD-43253 | biostudies-arrayexpress

Estimating Genome-wide Off-Target Effects for Pyrrole-Imidazole Polyamide Binding by a Pathway-Based Expression Profiling Approach

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-04-09 | GSE124462 | GEO

Antitumor activity of a pyrrole-imidazole polyamide.

Project description: Not available

| S-EPMC3562772 | biostudies-literature

Antitumor activity of a pyrrole-imidazole polyamide

2013-01-31 | GSE43253 | GEO

Direct Targeting of MYCN Gene Amplification by Alkylating Pyrrole-Imidazole Polyamide in Neuroblastoma Cells (CHP-134)

Project description:Amplification of MYCN plays a pivotal role in multiple types of tumors and correlates with poor prognosis in high-risk neuroblastoma. Despite recent advances in the treatment of neuroblastoma, no approaches directly target the master oncogene MYCN. Difficulties in targeting the MYCN protein have inspired us to develop a new gene level inhibitory strategy using a sequence-specific gene regulator. Here we generated a MYCN-targeting pyrrole-imidazole (PI) polyamide, MYCN-A3, which directly binds to and alkylates DNA at homing motifs within MYCN transcript. Pharmacological suppression of MYCN inhibited the proliferation of cancer cells harboring MYCN amplification compared with MYCN non-amplified cancer cells. In neuroblastoma xenograft mouse models, MYCN-A3 specifically downregulated MYCN expression and suppressed tumor progression with no detectable adverse effects and resulted in prolonged overall survival. Moreover, we observed the copy number reduction of MYCN in neuroblastoma cells with MYCN amplification upon treatment with MYCN-A3 but not MYCN non-targeting PI polyamide. Expression microarray experiments were also performed to compare the genome-wide effect of MYCN-A3 with CRISPR/Cas9 silencing of MYCN (MYCNcr-a).

2018-12-25 | GSE121528 | GEO

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