ERα and ERβ expression and transcriptional activity are differentially regulated by HDAC inhibitors

The proliferative action of ER alpha largely accounts for the carcinogenic activity of estrogens. By contrast, recent data show that ER beta 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 ER beta protein levels, whereas it decreased ER alpha 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 ER beta more strongly than that of ER alpha. 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 ER beta expression led to a dramatic increased in the antiproliferative activity of HDI, which correlated with a modi. cation of the transcription of genes involved in cell cycle control by HDI. Altogether, these data demonstrate that the interference of ER beta and HDAC on the control of transcription and cell proliferation constitute a promising approach for cancer therapy.