title: Epigenetic mechanisms of melatonin action in human SH-SY5Y neuroblastoma cells.
abstract: We have shown that melatonin induces histone hyperacetylation in vitro and in vivo. To clarify the mechanisms involved, we have now investigated its effects on histone acetylation and signaling pathways in human SH-SY5Y neuroblastoma cells, which express melatonin MT1 receptors. Melatonin caused significant concentration-dependent increases in both histone H3 and H4 acetylation. Blockade of melatonin receptors with luzindole abolished the histone hyperacetylating effect of melatonin, whereas inhibition of MAPK-ERK by PD98059 attenuated but did not block this effect. Melatonin treatment for 24-h decreased the levels of phospho-ERK1/2, but significantly increased Akt phosphorylation and protein expression of the histone acetyltransferase, p300. These findings suggest that the epigenetic effects of melatonin in SH-SY5Y cells are mediated by G protein-coupled MT1 melatonin receptors. Furthermore, upregulation of the histone acetyltransferase/transcriptional co-activator p300, along with phosphorylation of Akt, which is essential for p300 activation, appear to be key mechanisms underlying the epigenetic effects of melatonin.
authors.affiliation: Department of Psychiatry & Behavioural Neurosciences, McMaster University, Faculty of Health Sciences, HSC-4N77, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Psychiatry & Behavioural Neurosciences, McMaster University, Faculty of Health Sciences, HSC-4N77, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada. Electronic address: niles@mcmaster.ca.
authors.forename: Lennard P
authors.initials: LP
authors.lastname: Niles
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008550:Melatonin / Q000502:physiology*; D009447:Neuroblastoma; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014363:Tryptamines / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D006657:Histones; D008550:Melatonin; D051057:Proto-Oncogene Proteins c-akt; D044122:Receptor, Melatonin, MT1; D014363:Tryptamines; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C057154:luzindole
keywords: Epigenetic; Histone hyperacetylation; Melatonin MT(1) receptor; Phospho-Akt; p300