Abstract
The proliferative action of ERα largely accounts for the carcinogenic activity of estrogens. By contrast, recent data show that ERβ displays tumor-suppressor properties, thus supporting the interest to identify compounds that could increase its activity. Here, we show that histone deacetylase inhibitors (HDI) upregulated ERβ protein levels, whereas it decreased ERα expression. Part of this regulation took place at the mRNA level through a mechanism independent of de novo protein synthesis. In addition, we found that, in various cancer cells, the treatment with different HDI enhanced the ligand-dependent activity of ERβ more strongly than that of ERα. On the other hand, in MDA-MB231 and HeLa cells, the expression of ERs modified the transcriptional response to HDI. The use of deletion mutants of both receptors demonstrated that AF1 domain of the receptors was required. Finally, we show that ERβ expression led to a dramatic increased in the antiproliferative activity of HDI, which correlated with a modification of the transcription of genes involved in cell cycle control by HDI. Altogether, these data demonstrate that the interference of ERβ and HDAC on the control of transcription and cell proliferation constitute a promising approach for cancer therapy.
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Abbreviations
- ER:
-
estrogen receptor
- HDAC:
-
histone deacetylase
- HDI:
-
histone deacetylase inhibitor
- E2:
-
17β-estradiol
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Acknowledgements
We are grateful to S Bonnet and A Lucas for their technical help. We thank the Vector Core of the University Hospital of Nantes supported by the Association Française contre les Myopathies (AFM) for the production of Adenoviruses. This work was supported by grants from ARC (Association pour la Recherche contre le Cancer, Grant No. 3582; La ligue Nationale Contre le Cancer and from the National Institutes of Health (NIH CA18119). VD, RM and AL were recipient from the French Minister of Research. AL was also supported by the Ligue Nationale Contre le Cancer.
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Duong, V., Licznar, A., Margueron, R. et al. ERα and ERβ expression and transcriptional activity are differentially regulated by HDAC inhibitors. Oncogene 25, 1799–1806 (2006). https://doi.org/10.1038/sj.onc.1209102
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DOI: https://doi.org/10.1038/sj.onc.1209102
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