title: The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer.
abstract: Chromatin undergoes structural changes in response to extracellular and environmental signals. We observed changes in nuclear morphology in cancer tissue biopsied after chemotherapy and hypothesised that these DNA damage-induced changes are mediated by histone deacetylases (HDACs). Nuclear morphological changes in cell lines (PE01 and PE04 models) and a xenograft model (OV1002) were measured in response to platinum chemotherapy by image analysis of nuclear texture. HDAC2 expression increased in PEO1 cells treated with cisplatin at 24h, which was accompanied by increased expression of heterochromatin protein 1 (HP1). HDAC2 and HP1 expression were also increased after carboplatin treatment in the OV1002 carboplatin-sensitive xenograft model but not in the insensitive HOX424 model. Expression of DNA damage response pathways (pBRCA1, γH2AX, pATM, pATR) showed time-dependent changes after cisplatin treatment. HDAC2 knockdown by siRNA reduced HP1 expression, induced DNA double strand breaks (DSB) measured by γH2AX, and interfered with the activation of DNA damage response induced by cisplatin. Furthermore, HDAC2 depletion affected γH2AX foci formation, cell cycle distribution, and apoptosis triggered by cisplatin, and was additive to the inhibitory effect of cisplatin in cell lines. By inhibiting expression of HDAC2, reversible alterations in chromatin patterns during cisplatin treatment were observed. These results demonstrate quantifiable alterations in nuclear morphology after chemotherapy, and implicate HDAC2 in higher order chromatin changes and cellular DNA damage responses in ovarian cancer cells in vitro and in vivo.
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Rui
authors.initials: R
authors.lastname: Huang
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tse
authors.affiliation: School of Medicine, University of St Andrews, St Andrews, Fife KY16 9TF, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Mullen
authors.affiliation: School of Medicine, University of St Andrews, St Andrews, Fife KY16 9TF, UK.
authors.forename: In Hwa
authors.initials: IH
authors.lastname: Um
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Dana
authors.initials: D
authors.lastname: Faratian
authors.affiliation: School of Medicine, University of St Andrews, St Andrews, Fife KY16 9TF, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D005260:Female; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016190:Carboplatin; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D002945:Cisplatin
keywords: HDAC2; chromatin; ovarian cancer; platinum