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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, Steve Conlan, Johannes Zuber, Udo Jeschke, Fabian Trillsch, Philipp Rathert

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

Swansea University Authors: Lewis Francis, Steve Conlan

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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa57490
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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 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.
Keywords: non-genetic platinum resistance; MBD3; epithelial ovarian cancer; enhancer remodeling; biomarker; RNAi screen
College: Swansea University Medical School
Issue: 15
Start Page: 3801