ERalpha and ERbeta expression and transcriptional activity are differentially regulated by HDAC inhibitors

Oncogene. 2006 Mar 16;25(12):1799-806. doi: 10.1038/sj.onc.1209102.


The proliferative action of ERalpha largely accounts for the carcinogenic activity of estrogens. By contrast, recent data show that ERbeta 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 ERbeta protein levels, whereas it decreased ERalpha 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 ERbeta more strongly than that of ERalpha. 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 ERbeta 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 ERbeta and HDAC on the control of transcription and cell proliferation constitute a promising approach for cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Estrogen Receptor alpha / drug effects*
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / drug effects*
  • Estrogen Receptor beta / metabolism
  • HeLa Cells
  • Histone Deacetylases / drug effects
  • Histone Deacetylases / metabolism*
  • Humans
  • Polymerase Chain Reaction
  • RNA, Messenger
  • Transcription, Genetic / drug effects*


  • Enzyme Inhibitors
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • RNA, Messenger
  • Histone Deacetylases