Bauer Tabea L, Collmar Katrin, Kaltofen Till, Loeffler Ann-Katrin, Decker Lorena, Mueller Jan, Pinter Sabine, Eisler Stephan A, Mahner Sven, Fraungruber Patricia, Kommoss Stefan, Staebler Annette, Francis Lewis, Conlan R Steven, Zuber Johannes, Jeschke Udo, Trillsch Fabian, Rathert Philipp
Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, 70569 Stuttgart, Germany.
Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
Cancers (Basel). 2021 Jul 28;13(15):3801. doi: 10.3390/cancers13153801.
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.
上皮性卵巢癌（EOC）是女性生殖道中最致命的疾病，尽管大多数患者对基于铂（cPt）的化合物的初始治疗有反应，但复发却很常见。我们研究了表观遗传变化在对cPt敏感和耐药的EOC细胞系中的作用，发现它们的增强子图谱存在明显差异。临床数据显示，在耐药的EOC细胞系中获得大型增强子簇的两个基因（JAK1和FGF10）可为早期患者分层提供新的生物标志物，其中JAK1具有统计学独立性。为了调节增强子重塑过程并防止EOC细胞获得cPt耐药性，我们在存在cPt的情况下进行了染色质聚焦RNAi筛选。我们确定核小体重塑和去乙酰化酶（NuRD）复合物的亚基是使EOC细胞系A2780对铂治疗敏感的关键因素。抑制甲基化CpG结合域蛋白3（MBD3）可使细胞敏感，并通过改变增强子区域的H3K27ac来防止在长时间cPt暴露下产生耐药性，H3K27ac在cPt耐药细胞中受到差异调节从而导致侵袭性较低的表型。我们的工作确立了JAK1作为独立的预后标志物以及NuRD复合物作为联合治疗的潜在靶点。
