Abstract
Ets-1 is a transcription factor that regulates many genes involved in cancer progression and in tumour invasion. It is a poor prognostic marker for breast, lung, colorectal and ovary carcinomas. Here, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a novel interaction partner of Ets-1. We show that Ets-1 activates, by direct interaction, the catalytic activity of PARP-1 and is then poly(ADP-ribosyl)ated in a DNA-independent manner. The catalytic inhibition of PARP-1 enhanced Ets-1 transcriptional activity and caused its massive accumulation in cell nuclei. Ets-1 expression was correlated with an increase in DNA damage when PARP-1 was inhibited, leading to cancer cell death. Moreover, PARP-1 inhibitors caused only Ets-1-expressing cells to accumulate DNA damage. These results provide new insight into Ets-1 regulation in cancer cells and its link with DNA repair proteins. Furthermore, our findings suggest that PARP-1 inhibitors would be useful in a new therapeutic strategy that specifically targets Ets-1-expressing tumours.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Nucleus / genetics
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Cells, Cultured
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DNA Damage / genetics*
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Female
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Flow Cytometry
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Fluorescent Antibody Technique
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Humans
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Immunoprecipitation
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Mice
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Mice, Knockout
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Poly Adenosine Diphosphate Ribose / metabolism*
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism*
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Proto-Oncogene Protein c-ets-1 / genetics*
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Proto-Oncogene Protein c-ets-1 / metabolism
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RNA, Messenger / genetics
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Transcription, Genetic*
Substances
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ETS1 protein, human
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Poly(ADP-ribose) Polymerase Inhibitors
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Proto-Oncogene Protein c-ets-1
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RNA, Messenger
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Poly Adenosine Diphosphate Ribose
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Poly(ADP-ribose) Polymerases
Grants and funding
This work was supported by the Centre National de la Recherche Scientifique (CNRS) and by grants from la Ligue contre le Cancer, Comité du Pas-de-Calais. The Ministère de la Recherche et de l'Enseignement Supérieur and the Fondation ARC pour la Recherche sur le cancer provided a PhD fellowship to Arnaud J. Legrand. The CNRS and the Conseil Régional du Nord-Pas-de-Calais provided a PhD fellowship (BDI) to Souhaila Choul-li. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.