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Journal of Neural Transmission

, Volume 119, Issue 1, pp 17–24 | Cite as

Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells

  • Melinda Bence
  • Julia Koller
  • Maria Sasvari-Szekely
  • Gergely Keszler
Basic Neurosciences, Genetics and Immunology - Original Article

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.

Keywords

Trichostatin A Gene expression Monoamine reuptake transporters Neurotransmission Transcriptional regulation 

Abbreviations

COMT

Catechol-O-methyltransferase

DAT

Dopamine transporter

DBH

Dopamine hydroxylase

DRD3 and 4

Dopamine receptors D3 and D4

DRRF

Dopamine receptor regulating factor

FCS

Fetal calf serum

HGPRT

Hypoxanthine guanine phosphoribosyl transferase

HTR1A

Serotonin 1A receptor

MAO-A

Monoamine oxidase A

PBS

Phosphate buffered saline

RPLP0

P0 large ribosomal protein

SLC6A4

Serotonin transporter

TPH2

Tryptophan hydroxylase 2

TSA

Trichostatin A

VEGF

Vascular endothelial growth factor

Notes

Acknowledgments

This work was supported by the Hungarian national funds ETT 254 and OTKA T081466.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Melinda Bence
    • 1
  • Julia Koller
    • 1
  • Maria Sasvari-Szekely
    • 1
  • Gergely Keszler
    • 1
  1. 1.Department of Medical Chemistry, Molecular Biology and PathobiochemistrySemmelweis UniversityBudapestHungary

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