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

  • Basic Neurosciences, Genetics and Immunology - Original Article
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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.

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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

References

  • Bence M, Kereszturi E, Mozes V, Sasvari-Szekely M, Keszler G (2009) Hypoxia-induced transcription of dopamine D3 and D4 receptors in human neuroblastoma and astrocytoma cells. BMC Neurosci 10:92

    Article  PubMed  Google Scholar 

  • Chambers AE, Banerjee S, Chaplin T, Dunne J, Debernardi S, Joel SP, Young BD (2003) Histone acetylation-mediated regulation of genes in leukaemic cells. Eur J Cancer 39:1165–1175

    Article  PubMed  CAS  Google Scholar 

  • Chen K, Ou XM, Chen G, Choi SH, Shih JC (2005) R1, a novel repressor of the human monoamine oxidase A. J Biol Chem 280:11552–11559

    Article  PubMed  CAS  Google Scholar 

  • Codd R, Braich N, Liu J, Soe CZ, Pakchung AA (2009) Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. Int J Biochem Cell Biol 41:736–739

    Article  PubMed  CAS  Google Scholar 

  • Ellis DJ, Lawman ZK, Bonham K (2008) Histone acetylation is not an accurate predictor of gene expression following treatment with histone deacetylase inhibitors. Biochem Biophys Res Commun 367:656–662

    Article  PubMed  CAS  Google Scholar 

  • Ellis L, Hammers H, Pili R (2009) Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett 280:145–153

    Article  PubMed  CAS  Google Scholar 

  • Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1313–1323

    Article  PubMed  CAS  Google Scholar 

  • Fu J, Weise AM, Falany JL, Falany CN, Thibodeau BJ, Miller FR, Kocarek TA, Runge-Morris M (2010) Expression of estrogenicity genes in a lineage cell culture model of human breast cancer progression. Breast Cancer Res Treat 120:35–45

    Article  PubMed  CAS  Google Scholar 

  • Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60

    Article  PubMed  CAS  Google Scholar 

  • Haile CN, Kosten TR, Kosten TA (2009) Pharmacogenetic treatments for drug addiction: cocaine, amphetamine and methamphetamine. Am J Drug Alcohol Abuse 35:161–177

    Article  PubMed  Google Scholar 

  • Heils A, Wichems C, Mössner R, Petri S, Glatz K, Bengel D, Murphy DL, Lesch KP (1998) Functional characterization of the murine serotonin transporter gene promoter in serotonergic raphe neurons. J Neurochem 70:932–939

    Article  PubMed  CAS  Google Scholar 

  • Heo H, Yoo L, Shin KS, Kang SJ (2009) Suppression of caspase-11 expression by histone deacetylase inhibitors. Biochem Biophys Res Commun 378:79–83

    Article  PubMed  CAS  Google Scholar 

  • Her S, Lee MS, Morita K (2010) Trichostatin A stimulates steroid 5alpha-reductase gene expression in rat C6 glioma cells via a mechanism involving Sp1 and Sp3 transcription factors. J Mol Neurosci 41:252–262

    Article  PubMed  CAS  Google Scholar 

  • Kasper LH, Boussouar F, Boyd K, Xu W, Biesen M, Rehg J, Baudino TA, Cleveland JL, Brindle PK (2005) Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression. EMBO J 24:3846–3858

    Article  PubMed  CAS  Google Scholar 

  • Kawarai T, Kawakami H, Yamamura Y, Nakamura S (1997) Structure and organization of the gene encoding human dopamine transporter. Gene 195:11–18

    Article  PubMed  CAS  Google Scholar 

  • Kee HJ, Kook H (2009) Krüppel-like factor 4 mediates histone deacetylase inhibitor-induced prevention of cardiac hypertrophy. J Mol Cell Cardiol 47:770–780

    Article  PubMed  CAS  Google Scholar 

  • Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, Kim CW, Kim KW (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7:437–443

    Article  PubMed  Google Scholar 

  • Kong X, Fang M, Li P, Fang F, Xu Y (2009) HDAC2 deacetylates class II transactivator and suppresses its activity in macrophages and smooth muscle cells. J Mol Cell Cardiol 46:292–299

    Article  PubMed  CAS  Google Scholar 

  • Kouskouti A, Talianidis I (2005) Histone modifications defining active genes persist after transcriptional and mitotic inactivation. EMBO J 24:347–357

    Article  PubMed  CAS  Google Scholar 

  • Kwon HJ, Kim MS, Kim MJ, Nakajima H, Kim KW (2002) Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 97:290–296

    Article  PubMed  CAS  Google Scholar 

  • Lee KH, Kwak YD, Kim DH, Chang MY, Lee YS, Lee YS (2004) Human zinc finger protein 161, a novel transcriptional activator of the dopamine transporter. Biochem Biophys Res Commun 313:969–976

    Article  PubMed  CAS  Google Scholar 

  • Lin Z, Madras BK (2006) Human genetics and pharmacology of neurotransmitter transporters. Handb Exp Pharmacol 175:327–371

    Article  PubMed  CAS  Google Scholar 

  • Liu T, Tee AE, Porro A, Smith SA, Dwarte T, Liu PY, Iraci N, Sekyere E, Haber M, Norris MD, Diolaiti D, Della Valle G, Perini G, Marshall GM (2007) Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis. Proc Natl Acad Sci USA 104:18682–18687

    Article  PubMed  CAS  Google Scholar 

  • Marmorstein R, Trievel RC (2009) Histone modifying enzymes: structures, mechanisms, and specificities. Biochim Biophys Acta 1789:58–68

    PubMed  CAS  Google Scholar 

  • Martínez-Iglesias O, Ruiz-Llorente L, Sánchez-Martínez R, García L, Zambrano A, Aranda A (2008) Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clin Transl Oncol 10:395–398

    Article  PubMed  Google Scholar 

  • Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, Kaneda Y (2009) A histone H3 lysine 36 trimethyltransferase links Nkx2–5 to Wolf-Hirschhorn syndrome. Nature 460:287–291

    Article  PubMed  CAS  Google Scholar 

  • Park H, Lee YJ, Kim TH, Lee J, Yoon S, Choi WS, Myung CS, Kim HS (2008) Effects of trichostatin A, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells. Int J Mol Med 22:605–611

    PubMed  Google Scholar 

  • Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P, Pili R (2006) Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 66:8814–8821

    Article  PubMed  CAS  Google Scholar 

  • Romieu P, Host L, Gobaille S, Sandner G, Aunis D, Zwiller J (2008) Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats. J Neurosci 28:9342–9348

    Article  PubMed  CAS  Google Scholar 

  • Ronacher K, Hadley K, Avenant C, Stubsrud E, Simons SS Jr, Louw A, Hapgood JP (2009) Ligand-selective transactivation and transrepression via the glucocorticoid receptor: role of cofactor interaction. Mol Cell Endocrinol 299:219–231

    Article  PubMed  CAS  Google Scholar 

  • Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ (2001) Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem 76:1565–1572

    Article  PubMed  CAS  Google Scholar 

  • Samochowiec J, Rybakowski F, Czerski P, Zakrzewska M, Stepień G, Pełka-Wysiecka J, Horodnicki J, Rybakowski JK, Hauser J (2001) Polymorphisms in the dopamine, serotonin, and norepinephrine transporter genes and their relationship to temperamental dimensions measured by the Temperament and Character Inventory in healthy volunteers. Neuropsychobiology 43:248–253

    Article  PubMed  CAS  Google Scholar 

  • Sawa H, Murakami H, Ohshima Y, Murakami M, Yamazaki I, Tamura Y, Mima T, Satone A, Ide W, Hashimoto I, Kamada H (2002) Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit vascular endothelial growth factor (VEGF) secretion from human glioblastoma cells. Brain Tumor Pathol 19:77–81

    Article  PubMed  CAS  Google Scholar 

  • Senese S, Zaragoza K, Minardi S, Muradore I, Ronzoni S, Passafaro A, Bernard L, Draetta GF, Alcalay M, Seiser C, Chiocca S (2007) Role for histone deacetylase 1 in human tumor cell proliferation. Mol Cell Biol 27:4784–4795

    Article  PubMed  CAS  Google Scholar 

  • Seo HW, Kim EJ, Na H, Lee MO (2009) Transcriptional activation of hypoxia-inducible factor-1alpha by HDAC4 and HDAC5 involves differential recruitment of p300 and FIH-1. FEBS Lett 583:55–60

    Article  PubMed  CAS  Google Scholar 

  • Soutoglou E, Papafotiou G, Katrakili N, Talianidis I (2000) Transcriptional activation by hepatocyte nuclear factor-1 requires synergism between multiple coactivator proteins. J Biol Chem 275:12515–12520

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Bannon MJ (2005) Sp1 and Sp3 activate transcription of the human dopamine transporter gene. J Neurochem 93:474–482

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Michelhaugh SK, Bannon MJ (2007) Valproate robustly increases Sp transcription factor-mediated expression of the dopamine transporter gene within dopamine cells. Eur J Neurosci 25:1982–1986

    Article  PubMed  Google Scholar 

  • Woo HJ, Lee SJ, Choi BT, Park YM, Choi YH (2007) Induction of apoptosis and inhibition of telomerase activity by trichostatin A, a histone deacetylase inhibitor, in human leukemic U937 cells. Exp Mol Pathol 82:77–84

    Article  PubMed  CAS  Google Scholar 

  • Yang QC, Zeng BF, Shi ZM, Dong Y, Jiang ZM, Huang J, Lv YM, Yang CX, Liu YW (2006) Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma. J Exp Clin Cancer Res 25:593–599

    PubMed  CAS  Google Scholar 

  • Yoo AS, Crabtree GR (2009) ATP-dependent chromatin remodeling in neural development. Curr Opin Neurobiol 19:120–126

    Article  PubMed  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, POB 260, Budapest, 1444, Hungary

    Melinda Bence, Julia Koller, Maria Sasvari-Szekely & Gergely Keszler

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  1. Melinda Bence
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  2. Julia Koller
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  3. Maria Sasvari-Szekely
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  4. Gergely Keszler
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Correspondence to Gergely Keszler.

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Bence, M., Koller, J., Sasvari-Szekely, M. et al. Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells. J Neural Transm 119, 17–24 (2012). https://doi.org/10.1007/s00702-011-0688-4

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  • DOI: https://doi.org/10.1007/s00702-011-0688-4

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