title: Genomic DNA hypomethylation by histone deacetylase inhibition implicates DNMT1 nuclear dynamics.
abstract: Histone deacetylase inhibitors (HDACi) are promising antitumor drugs acting through reactivation of silenced tumor suppressor genes. Several HDACi are currently in clinical trials both for hematological and solid tissue malignancies. Cooperative action of HDACi and DNA methylation inhibitors (DNMTi) has been reported, making combined treatment an attractive choice for cancer therapy. There is some evidence that synergistic effects of HDACi and DNMTi are achieved by their action on common targets, including DNA methyltransferase 1 (DNMT1). To further analyze this interaction, we investigated the effect of the HDACi trichostatin A on global and gene-specific DNA methylation and applied methods with single molecule sensitivity, confocal laser scanning microscopy with avalanche photodiode detectors (APD imaging) and fluorescence correlation spectroscopy (FCS), to study its effect on the nuclear dynamics of DNMT1 in live cells. Our data show that trichostatin A treatment reduces global DNA methylation and the DNMT1 protein level and alters DNMT1 nuclear dynamics and interactions with chromatin. The mechanisms underlying these effects are apparently distinct from the mechanisms of action of the DNMT inhibitor 5-azacytidine. Our study sheds light on the molecular mechanisms underlying the synergistic action of HDACi and DNMTi and may also help to define improved policies for cancer treatment.
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Mohsen Karimi
authors.initials: MK
authors.lastname: Arzenani
authors.forename: Atosa Esteki
authors.initials: AE
authors.lastname: Zade
authors.forename: Yu
authors.initials: Y
authors.lastname: Ming
authors.forename: Susanne J H
authors.initials: SJ
authors.lastname: Vijverberg
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zahidul
authors.initials: Z
authors.lastname: Khan
authors.forename: Syed
authors.initials: S
authors.lastname: Sadique
authors.forename: Lorenz
authors.initials: L
authors.lastname: Kallenbach
authors.forename: LiFu
authors.initials: L
authors.lastname: Hu
authors.forename: Vladana
authors.initials: V
authors.lastname: Vukojević
authors.forename: Tomas J
authors.initials: TJ
authors.lastname: Ekström
mesh_terms: D001374:Azacitidine / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020033:Protein Isoforms; C012589:trichostatin A; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D006655:Histone Deacetylases; D001374:Azacitidine