A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells

Saverio Minucci, Valerie Horn, Nisan Bhattacharyya, Valya Russanova, Vasily V. Ogryzko, Lucia Gabriele, Bruce H. Howard, Keiko Ozato

Research output: Contribution to journalArticle

Abstract

Histone acetylation is thought to have a role in transcription. To gain insight into the role of histone acetylation in retinoid-dependent transcription, we studied the effects of trichostatin A (TSA), a specific inhibitor of histone deacetylase, on P19 embryonal carcinoma cells. We show that coaddition of TSA and retinoic acid (RA) markedly enhances neuronal differentiation in these cells, although TSA alone does no induce differentiation but causes extensive apoptosis. Consistent with the cooperative effect of TSA and RA, coaddition of the two agents synergistically enhanced transcription from stably integrated RA-responsive promoters. The transcriptional synergy by TSA and RA required the RA- responsive element and a functional retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimer, both obligatory for RA dependent transcription. Furthermore, TSA led to promoter activation by an RXR-selective ligand that was otherwise inactive in transcription. In addition, TSA enhanced transcription from a minimum basal promoter, independently of the RA- responsive element. Finally, we show that TSA alone or in combination with RA increases in vivo endonuclease activity within the RA-responsive promoter, suggesting that TSA treatment might alter a local chromatin environment to enhance RXR/RAR heterodimer action. Thus, these results indicate that histone acetylation influences activity of the heterodimer, which is line with the observed interaction between the RXR/RAR heterodimer and a histone acetylase presented elsewhere.

Original languageEnglish
Pages (from-to)11295-11300
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number21
DOIs
Publication statusPublished - Oct 14 1997

    Fingerprint

ASJC Scopus subject areas

  • Genetics
  • General

Cite this