The histone deacetylase inhibitor trichostatin A induces GADD45 gamma expression via Oct and NF-Y binding sites.
The GADD45gamma protein is a potential tumor suppressor whose expression is reduced in several tumors. However, very little is known about the regulation of its expression. We have determined that the most relevant region of its promoter lies between nucleotides -112 and -54, relative to the transcription start site. Putative Oct and NF-Y elements were found in this region and factors belonging to these families interacted with these elements in vitro and with the promoter in vivo. Mutation of these elements reduced the basal activity of the promoter, suggesting that both sites are essential for basal expression. These factors interact with chromatin modifying proteins and we found that histone deacetylase 1 or silencing mediator for retinoid and thyroid hormone receptor overexpression reduced the basal activity of the promoter. In contrast, forced expression of the histone acetylase protein PCAF or cell treatment with the HDAC inhibitor trichostatin A increased GADD45gamma mRNA levels and induced GADD45gamma promoter activity through its Oct and NF-Y elements. Moreover, ectopic expression of a dominant-negative version of NF-YA strongly inhibited trichostatin A-induced activation of the promoter. Our data strongly suggest that inhibition of deacetylase activity could potentially be used for treatment of tumors where GADD45gamma expression is reduced.
Campanero
M R
MR
Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier, Madrid, Spain.
Herrero
A
A
Calvo
V
V
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D023081:CCAAT-Binding Factor / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D050810:Octamer Transcription Factors / Q000378:metabolism* / Q000502:physiology; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000502:physiology; D017384:Sequence Deletion; D000097642:GADD45 Proteins
D023081:CCAAT-Binding Factor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D050810:Octamer Transcription Factors; C485654:GADD45G protein, human; D000097642:GADD45 Proteins; C012589:trichostatin A