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The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer

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 morpholog...

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Autores principales: Huang, Rui, Langdon, Simon P, Tse, Matthew, Mullen, Peter, Um, In Hwa, Faratian, Dana, Harrison, David J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826236/
https://www.ncbi.nlm.nih.gov/pubmed/26683361
http://dx.doi.org/10.18632/oncotarget.6618
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author Huang, Rui
Langdon, Simon P
Tse, Matthew
Mullen, Peter
Um, In Hwa
Faratian, Dana
Harrison, David J
author_facet Huang, Rui
Langdon, Simon P
Tse, Matthew
Mullen, Peter
Um, In Hwa
Faratian, Dana
Harrison, David J
author_sort Huang, Rui
collection PubMed
description 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.
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spelling pubmed-48262362016-05-09 The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer Huang, Rui Langdon, Simon P Tse, Matthew Mullen, Peter Um, In Hwa Faratian, Dana Harrison, David J Oncotarget Research Paper 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. Impact Journals LLC 2015-12-14 /pmc/articles/PMC4826236/ /pubmed/26683361 http://dx.doi.org/10.18632/oncotarget.6618 Text en Copyright: © 2016 Huang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Huang, Rui
Langdon, Simon P
Tse, Matthew
Mullen, Peter
Um, In Hwa
Faratian, Dana
Harrison, David J
The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer
title The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer
title_full The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer
title_fullStr The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer
title_full_unstemmed The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer
title_short The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer
title_sort role of hdac2 in chromatin remodelling and response to chemotherapy in ovarian cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826236/
https://www.ncbi.nlm.nih.gov/pubmed/26683361
http://dx.doi.org/10.18632/oncotarget.6618
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