title: Epigenetically induced changes in nuclear textural patterns and gelatinase expression in human fibrosarcoma cells.
abstract: OBJECTIVE
  Chromatin texture patterns of tumour cell nuclei can serve as cancer biomarkers, either to define diagnostic classifications or to obtain relevant prognostic information, in a large number of human tumours. Epigenetic mechanisms, mainly DNA methylation and histone post-translational modification, have been shown to influence chromatin packing states, and therefore nuclear texture. The aim of this study was to analyse effects of these two mechanisms on chromatin texture, and also on correlation with gelatinase expression, in human fibrosarcoma tumour cells.
  
  
  METHODS
  We investigated effects of DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-azadC) and histone deacetylase inhibitor trichostatin A (TSA) on nuclear textural characteristics of human HT1080 fibrosarcoma cells, evaluated by image cytometry, and expression of gelatinases MMP-2 and MMP-9, two metalloproteinases implicated in cancer progression and metastasis.
  
  
  RESULTS
  5-azadC induced significant variation in chromatin higher order organization, particularly chromatin decondensation, associated with reduction in global DNA methylation, concomitantly with increase in MMP-9, and to a lesser extent, MMP-2 expression. TSA alone did not have any effect on HT1080 cells, but exhibited differential activity when added to cells treated with 5-azadC. When treated with both drugs, nuclei had higher texture abnormalities. In this setting, reduction in MMP-9 expression was observed, whereas MMP-2 expression remained unaffected.
  
  
  CONCLUSIONS
  These data show that hypomethylating drug 5-azadC and histone deacetylase inhibitor TSA were able to induce modulation of higher order chromatin organization and gelatinase expression in human HT1080 fibrosarcoma cells.
authors.affiliation: Unité MEDyC, URCA-CNRS FRE 3481, SFR Cap-Santé, Faculté de Pharmacie, Université de Reims, Reims, France.
authors.forename: M
authors.initials: M
authors.lastname: Poplineau
authors.forename: C
authors.initials: C
authors.lastname: Doliwa
authors.forename: M
authors.initials: M
authors.lastname: Schnekenburger
authors.forename: F
authors.initials: F
authors.lastname: Antonicelli
authors.forename: M
authors.initials: M
authors.lastname: Diederich
authors.forename: A
authors.initials: A
authors.lastname: Trussardi-Régnier
authors.forename: J
authors.initials: J
authors.lastname: Dufer
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019175:DNA Methylation; D000077209:Decitabine; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019044:Image Cytometry; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; C012589:trichostatin A; D000077209:Decitabine; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D001374:Azacitidine