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Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development

Tabea L. Bauer, Katrin Collmar, Till Kaltofen, Ann-Katrin Loeffler, Lorena Decker, Jan Mueller, Sabine Pinter, Stephan A. Eisler, Sven Mahner, Patricia Fraungruber, Stefan Kommoss, Annette Staebler, Lewis Francis Orcid Logo, Steve Conlan Orcid Logo, Johannes Zuber, Udo Jeschke, Fabian Trillsch, Philipp Rathert

Cancers, Volume: 13, Issue: 15, Start page: 3801

Swansea University Authors: Lewis Francis Orcid Logo, Steve Conlan Orcid Logo

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DOI (Published version): 10.3390/cancers13153801

Abstract

Epithelial ovarian cancer (EOC) is the most lethal disease of the female reproductive tract, and although most patients respond to the initial treatment with platinum (cPt)-based compounds, relapse is very common. We investigated the role of epigenetic changes in cPt-sensitive and -resistant EOC cel...

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Published in: Cancers
ISSN: 2072-6694
Published: MDPI AG 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa57490
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We investigated the role of epigenetic changes in cPt-sensitive and -resistant EOC cell lines and found distinct differences in their enhancer landscape. Clinical data revealed that two genes (JAK1 and FGF10), which gained large enhancer clusters in resistant EOC cell lines, could provide novel biomarkers for early patient stratification with statistical independence for JAK1. To modulate the enhancer remodeling process and prevent the acquisition of cPt resistance in EOC cells, we performed a chromatin-focused RNAi screen in the presence of cPt. We identified subunits of the Nucleosome Remodeling and Deacetylase (NuRD) complex as critical factors sensitizing the EOC cell line A2780 to platinum treatment. Suppression of the Methyl-CpG Binding Domain Protein 3 (MBD3) sensitized cells and prevented the establishment of resistance under prolonged cPt exposure through alterations of H3K27ac at enhancer regions, which are differentially regulated in cPt-resistant cells, leading to a less aggressive phenotype. 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spelling 2021-09-07T14:43:13.0085297 v2 57490 2021-08-02 Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 2021-08-02 BMS Epithelial ovarian cancer (EOC) is the most lethal disease of the female reproductive tract, and although most patients respond to the initial treatment with platinum (cPt)-based compounds, relapse is very common. We investigated the role of epigenetic changes in cPt-sensitive and -resistant EOC cell lines and found distinct differences in their enhancer landscape. Clinical data revealed that two genes (JAK1 and FGF10), which gained large enhancer clusters in resistant EOC cell lines, could provide novel biomarkers for early patient stratification with statistical independence for JAK1. To modulate the enhancer remodeling process and prevent the acquisition of cPt resistance in EOC cells, we performed a chromatin-focused RNAi screen in the presence of cPt. We identified subunits of the Nucleosome Remodeling and Deacetylase (NuRD) complex as critical factors sensitizing the EOC cell line A2780 to platinum treatment. Suppression of the Methyl-CpG Binding Domain Protein 3 (MBD3) sensitized cells and prevented the establishment of resistance under prolonged cPt exposure through alterations of H3K27ac at enhancer regions, which are differentially regulated in cPt-resistant cells, leading to a less aggressive phenotype. Our work establishes JAK1 as an independent prognostic marker and the NuRD complex as a potential target for combinational therapy. Journal Article Cancers 13 15 3801 MDPI AG 2072-6694 non-genetic platinum resistance; MBD3; epithelial ovarian cancer; enhancer remodeling; biomarker; RNAi screen 28 7 2021 2021-07-28 10.3390/cancers13153801 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Other Financial support was provided by the German Cancer Aid for Fabian Trillsch and Philipp Rathert (#70113426 and #70113433). 2021-09-07T14:43:13.0085297 2021-08-02T10:19:58.7869216 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Tabea L. Bauer 1 Katrin Collmar 2 Till Kaltofen 3 Ann-Katrin Loeffler 4 Lorena Decker 5 Jan Mueller 6 Sabine Pinter 7 Stephan A. Eisler 8 Sven Mahner 9 Patricia Fraungruber 10 Stefan Kommoss 11 Annette Staebler 12 Lewis Francis 0000-0002-7803-7714 13 Steve Conlan 0000-0002-2562-3461 14 Johannes Zuber 15 Udo Jeschke 16 Fabian Trillsch 17 Philipp Rathert 18 57490__20665__bab19faacba94c59aed7a7f7b749f7c5.pdf 57490.pdf 2021-08-18T15:27:48.3216990 Output 17858105 application/pdf Version of Record true © 2021 by the authors. This is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development
spellingShingle Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development
Lewis Francis
Steve Conlan
title_short Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development
title_full Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development
title_fullStr Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development
title_full_unstemmed Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development
title_sort Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development
author_id_str_mv 10f61f9c1248951c1a33f6a89498f37d
0bb6bd247e32fb4249de62c0013b51cb
author_id_fullname_str_mv 10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
author Lewis Francis
Steve Conlan
author2 Tabea L. Bauer
Katrin Collmar
Till Kaltofen
Ann-Katrin Loeffler
Lorena Decker
Jan Mueller
Sabine Pinter
Stephan A. Eisler
Sven Mahner
Patricia Fraungruber
Stefan Kommoss
Annette Staebler
Lewis Francis
Steve Conlan
Johannes Zuber
Udo Jeschke
Fabian Trillsch
Philipp Rathert
format Journal article
container_title Cancers
container_volume 13
container_issue 15
container_start_page 3801
publishDate 2021
institution Swansea University
issn 2072-6694
doi_str_mv 10.3390/cancers13153801
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Epithelial ovarian cancer (EOC) is the most lethal disease of the female reproductive tract, and although most patients respond to the initial treatment with platinum (cPt)-based compounds, relapse is very common. We investigated the role of epigenetic changes in cPt-sensitive and -resistant EOC cell lines and found distinct differences in their enhancer landscape. Clinical data revealed that two genes (JAK1 and FGF10), which gained large enhancer clusters in resistant EOC cell lines, could provide novel biomarkers for early patient stratification with statistical independence for JAK1. To modulate the enhancer remodeling process and prevent the acquisition of cPt resistance in EOC cells, we performed a chromatin-focused RNAi screen in the presence of cPt. We identified subunits of the Nucleosome Remodeling and Deacetylase (NuRD) complex as critical factors sensitizing the EOC cell line A2780 to platinum treatment. Suppression of the Methyl-CpG Binding Domain Protein 3 (MBD3) sensitized cells and prevented the establishment of resistance under prolonged cPt exposure through alterations of H3K27ac at enhancer regions, which are differentially regulated in cPt-resistant cells, leading to a less aggressive phenotype. Our work establishes JAK1 as an independent prognostic marker and the NuRD complex as a potential target for combinational therapy.
published_date 2021-07-28T04:13:16Z
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