Inhibition of Histone Deacetylase Activity Causes Cell Type-Specific Induction of the PDGF-B Promoter Only in the Absence of Activation by Its Enhancer

• Published in: Experimental cell research 2001-11, Vol.270 (2), p.188-198
• Main Authors: Ullerås, Erik, Miller, Stephen J., Adam, Gail I.R., Kanduri, Chandrasekhar, Wilcock, Arwen C., Franklin, Gary C.
• Format: Article
• Language: English
• Subjects: acetylation; Adenocarcinoma; Breast Neoplasms; Carcinoma, Hepatocellular; Choriocarcinoma; Chromosomes; DNA Methylation; Enhancer Elements (Genetics)/physiology; Enhancer Elements, Genetic - physiology; Enzyme Inhibitors - pharmacology; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - physiology; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; Histone Deacetylases/antagonists & inhibitors/metabolism; Humans; Hydroxamic Acids - pharmacology; Introns; Liver Neoplasms; Mutagenesis - physiology; PDGF-B; Promoter Regions (Genetics)/physiology; Promoter Regions, Genetic - physiology; Proto-Oncogene Proteins c-sis - genetics; Rhabdomyosarcoma; silencing; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; trichostatin A; Tumor Cells, Cultured
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1006/excr.2001.5338

There is a strong correlation between the acetylation status of nucleosomal histones and transcriptional activity. Here we show that the histone deacetylase inhibitor trichostatin A (TSA) activates reporter gene constructs driven by the human platelet-derived growth factor B (PDGF-B) gene promoter. This activation showed an inverse correlation with the cell type-specific transcriptional activities of the promoter. The TSA response was minimal in three tumor cell lines that exhibit high-level promoter activity. In JEG-3 choriocarcinoma cells, however, where the basal promoter activity is considerably lower, there was a strong response to TSA. This was in contrast to constructs that included a PDGF-B enhancer, which were refractory to TSA effects, indicating a possible function of the enhancer in modulating acetylation status. Analysis of PDGF-B promoter mutants with respect to TSA induction revealed no specific TSA-responsive element, but suggested that association of nonacetylated histones to the PDGF-B promoter may be a default process in the absence of enhancer activation. TSA treatment of JEG-3 cells, either alone or in combination with the demethylating agent 5-azacytidine, failed to activate the silenced endogenous PDGF-B transcript, however, which appears to be repressed by additional mechanisms.