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

SIMPLE SUMMARY: Most epithelial ovarian cancer (EOC) patients, although initially responsive to standard treatment with platinum-based chemotherapy, develop platinum resistance over the clinical course and succumb due to drug-resistant metastases. It has long been hypothesized that resistance to platinum develops as a result of epigenetic changes within tumor cells evolving over time. In this study, we investigated epigenomic changes in EOC patient samples, as well as in cell lines, and showed that profound changes at enhancers result in a platinum-resistant phenotype. Through correlation of the epigenomic alterations with changes in the transcriptome, we could identify potential novel prognostic biomarkers for early patient stratification. Furthermore, we applied a combinatorial RNAi screening approach to identify suitable targets that prevent the enhancer remodeling process. Our results advance the molecular understanding of epigenetic mechanisms in EOC and therapy resistance, which will be essential for the further exploration of epigenetic drug targets and combinatorial treatment regimes. 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.