Super-Enhancer Redistribution as a Mechanism of Broad Gene Dysregulation in Repeatedly Drug-Treated Cancer Cells

Anticancer drugs with narrow therapeutic window, such as cisplatin, are administrated at suboptimal and intermittent doses to limit their adverse effects in patients. This regimen may allow survival of cancer cells that problematically also gain malignancy as result of the treatment. Here, we describe a multilayered analysis ranging from chromatin to translation (based on ChIP-seq, GRO-seq, RNA-seq, and ribosome profiling) to comprehensively understand how cisplatin confers new cellular properties in a well-established ovarian cancer model of cisplatin exposure. This approach allowed us to segregate the human transcriptome into seventeen modules underlying distinct regulatory principles. The most robustly disrupted modules are primarily associated with super-enhancer reprogramming, induced after cells repeatedly initiate but fail to complete the process of drug-stimulated death (corroborated by CRISPRi/a technology after PageRank-based prediction of candidate mediators). We therefore propose that cisplatin provides survivor cells with new properties, paradoxically, when they undergo a drug-stimulated near to death experience.