Title :

Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines

Author(s) :

Nhili, Raja [Auteur]
Peixoto, Paul [Auteur]
Depauw, Sabine [Auteur]
Flajollet, Sebastien [Auteur]
Dezitter, Xavier [Auteur]
Munde, Manoj M. [Auteur]
Ismail Mohamed, A. [Auteur]
Kumar, Arvind [Auteur]
Faraha, Abdelbasset A. [Auteur]
Stephens, Chad E. [Auteur]
Duterque-Coquillaud, Martine [Auteur]
Wilson W., David [Auteur]
Boykin, David W. [Auteur]
David-Cordonnier, Marie-Helene [Auteur]

Journal title :

Nucleic acids research

Abbreviated title :

Nucleic Acids Res.

Volume number :

41

Pages :

125-138

Publication date :

2013-01-01

ISSN :

0305-1048

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Direct modulation of gene expression by targeting oncogenic transcription factors is a new area of research for cancer treatment. ERG, an ETS-family transcription factor, is commonly over-expressed or translocated in ...
Show more >Direct modulation of gene expression by targeting oncogenic transcription factors is a new area of research for cancer treatment. ERG, an ETS-family transcription factor, is commonly over-expressed or translocated in leukaemia and prostate carcinoma. In this work, we selected the di-(thiophene-phenyl-amidine) compound DB1255 as an ERG/DNA binding inhibitor using a screening test of synthetic inhibitors of the ERG/DNA interaction followed by electrophoretic mobility shift assays (EMSA) validation. Spectrometry, footprint and biosensor-surface plasmon resonance analyses of the DB1255/DNA interaction evidenced sequence selectivity and groove binding as dimer. Additional EMSA evidenced the precise DNA-binding sequence required for optimal DB1255/DNA binding and thus for an efficient ERG/DNA complex inhibition. We further highlighted the structure activity relationships from comparison with derivatives. In cellulo luciferase assay confirmed this modulation both with the constructed optimal sequences and the Osteopontin promoter known to be regulated by ERG and which ERG-binding site was protected from DNaseI digestion on binding of DB1255. These data showed for the first time the ERG/DNA complex modulation, both in vitro and in cells, by a heterocyclic diamidine that specifically targets a portion of the ERG DNA recognition site.Show less >

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
Inserm
Université de Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Research team(s) :

Therapeutic innovation targetting inflammation

Submission date :

2019-05-17T13:08:42Z