A HISTONE DEACETYLASE INHIBITOR POTENTIATES RETINOID RECEPTOR ACTION IN EMBRYONAL CARCINOMA-CELLS

Histone acetylation is thought to have a role in transcription, To gai n insight into the role of histone acetylation in retinoid-dependent t ranscription, we studied the effects of trichostatin A (TSA), a specif ic inhibitor of histone deacetylase, on P19 embryonal carcinoma cells, We show that coaddition of TSA and retinoic acid (RA) markedly enhanc es neuronal differentiation in these cells, although TSA alone does no t induce differentiation but causes extensive apoptosis, Consistent wi th the cooperative effect of TSA and RA, coaddition of the two agents synergistically enhanced transcription from stably integrated RA-respo nsive promoters, The transcriptional synergy by TSA and RA required th e RA-responsive element and a functional retinoid X receptor (RXR)/ret inoic acid receptor (RAR) heterodimer, both obligatory for RA-dependen t transcription, Furthermore, TSA led to promoter activation by an RXR -selective ligand that was otherwise inactive in transcription, In add ition, TSA enhanced transcription from a minimum basal promoter, indep endently of the RA-responsive element, Finally, we show that TSA alone or in combination with RA increases in vivo endonuclease sensitivity within the RA-responsive promoter, suggesting that TSA treatment might alter a local chromatin environment to enhance RXR/RAR heterodimer ac tion, Thus, these results indicate that histone acetylation influences activity of the heterodimer, which is in line with the observed inter action between the RXR/RAR heterodimer and a histone acetylase present ed elsewhere.