title: DNA methyltransferase inhibitor RG108 and histone deacetylase inhibitors cooperate to enhance NB4 cell differentiation and E-cadherin re-expression by chromatin remodelling.
abstract: Epigenetic silencing of cancer-related genes by abnormal methylation and the reversal of this process by DNA methylation inhibitors represents a promising strategy in cancer therapy. As DNA methylation affects gene expression and chromatin structure, we investigated the effects of novel DNMT (DNA methyltransferase) inhibitor, RG108, alone and in its combinations with structurally several HDAC (histone deacetylase) inhibitors [sodium PB (phenyl butyrate) or BML-210 (N-(2-aminophenyl)-N'phenyloctanol diamine), and all-trans RA (retinoic acid)] in the human PML (promyelocytic leukaemia) NB4 cells. RG108 at different doses from 20 to 100 μM caused time-, but not a dose-dependent inhibition of NB4 cell proliferation without cytotoxicity. Temporal pretreatment with RG108 before RA resulted in a dose-dependent cell growth inhibition and remarkable acceleration of granulocytic differentiation. Prolonged treatments with RG108 and RA in the presence of HDAC inhibitors significantly increased differentiation. RG108 caused time-dependent re-expression of methylation-silenced E-cadherin, with increase after temporal or continuous treatments with RG108 and RA, or RA together with PB in parallel, in cell maturation, suggesting the role of E-cadherin as a possible therapeutic marker. These processes required both PB-induced hyperacetylation of histone H4 and trimethylation of histone H3 at lysine 4, indicating the cooperative action of histone modifications and DNA methylation/demethylation in derepression of E-cadherin. This work provides novel experimental evidence of the beneficial role of the DNMT inhibitor RG108 in combinations with RA and HDACIs in the effective differentiation of human PML based on epigenetics.
authors: Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Mokslininku Street 12, LT08662, Vilnius, Lithuania.
authors: Jurate
authors: J
authors: Savickiene
authors: Grazina
authors: G
authors: Treigyte
authors: Arune
authors: A
authors: Jazdauskaite
authors: Veronika-Viktorija
authors: VV
authors: Borutinskaite
authors: Ruta
authors: R
authors: Navakauskiene
mesh_terms: D000813:Anilides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology; D010797:Phthalimides; D011422:Propionates / Q000494:pharmacology*; D013997:Time Factors; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives
chemical_list: D000813:Anilides; D015415:Biomarkers; D039481:CD11b Antigen; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C509295:ITGAM protein, human; D007211:Indoles; C514580:N1-(2-aminophenyl)-N8-phenyloctanediamide; D010654:Phenylbutyrates; D010797:Phthalimides; D011422:Propionates; C503639:RG108; D014212:Tretinoin; D014364:Tryptophan; D006655:Histone Deacetylases