title: Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells.
abstract: Histone deacetylase inhibitors are promising anti-tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies. However, little is known about any effects of these drugs on the central nervous system. The aim of the present study was to analyze the effects of trichostatin A (TSA)--a broad-spectrum histone deacetylase inhibitor--on the transcriptional regulation of several genes involved in dopamine- and serotonergic neurotransmission. To this end, short-term parallel cultures of SK-NF-I neuroblastoma cells were treated with TSA either alone or in combination with hypoxia, and mRNA levels of dopamine receptor D3 (DRD3) and D4 (DRD4), dopamine transporter (DAT), dopamine hydroxylase (DBH), dopamine receptor regulating factor (DRRF), catechol-O-methyltransferase (COMT), serotonin receptor 1A (HTR1A), monoamino oxidase A (MAO-A), serotonin transporter (SLC6A4) and tryptophan hydroxylase 2 (TPH2) were determined by quantitative PCR. We found that TSA did not antagonize the hypoxia-induced activation of D3 and D4 dopamine receptor genes, implying that induction of these genes is not mediated directly by hypoxia inducible factor-1alpha. On the other hand, TSA dramatically upregulated the expression of DAT and SLC6A4 (45-fold and 15-fold, respectively), while transcript levels of MAO-A and COMT were significantly reduced (by 70% and by more than 90%, respectively). Induction of DAT protein expression was detected by western blotting. These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons.
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, POB 260, Budapest 1444, Hungary.
authors.forename: Melinda
authors.initials: M
authors.lastname: Bence
authors.forename: Julia
authors.initials: J
authors.lastname: Koller
authors.forename: Maria
authors.initials: M
authors.lastname: Sasvari-Szekely
authors.forename: Gergely
authors.initials: G
authors.lastname: Keszler
mesh_terms: D015306:Biogenic Monoamines / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008995:Monoamine Oxidase / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D050483:Dopamine Plasma Membrane Transport Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D042461:Vascular Endothelial Growth Factor A; C012589:trichostatin A; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase