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, R. Steven Conlan, Johannes Zuber, Udo Jeschke, Fabian Trillsch, Philipp Rathert

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number3801
JournalCancers
Volume13
Issue number15
DOIs
StatePublished - Aug 1 2021

Keywords

  • Biomarker
  • Enhancer remodeling
  • Epithelial ovarian cancer
  • MBD3
  • Non‐genetic platinum resistance
  • RNAi screen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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