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

Cisplatin is an antineoplastic drug administered at suboptimal and intermittent doses to avoid life-threatening effects. Although this regimen shortly improves symptoms in the short term, it also leads to more malignant disease in the long term. We describe a multilayered analysis ranging from chromatin to translation—integrating chromatin immunoprecipitation sequencing (ChIP-seq), global run-on sequencing (GRO-seq), RNA sequencing (RNA-seq), and ribosome profiling—to understand how cisplatin confers (pre)malignant features by using a well-established ovarian cancer model of cisplatin exposure. This approach allows us to segregate the human transcriptome into gene modules representing distinct regulatory principles and to characterize that the most cisplatin-disrupted modules are associated with underlying events of super-enhancer plasticity. These events arise when cancer cells initiate without ultimately ending the program of drug-stimulated death. Using a PageRank-based algorithm, we predict super-enhancer regulator ISL1 as a driver of this plasticity and validate this prediction by using CRISPR/dCas9-KRAB inhibition (CRISPRi) and CRISPR/dCas9-VP64 activation (CRISPRa) tools. Together, we propose that cisplatin reprograms cancer cells when inducing them to undergo near-to-death experiences. [Display omitted] •A 6-layered multiomic approach provides an integrated view of cisplatin treatment•Repeated cisplatin treatment leads to selective super-enhancer (SE) redistribution•The most cisplatin-dysregulated genes locate nearby redistributed SE regions•ISL1 is a SE regulator suppressed when cells struggle with cisplatin treatment Ovarian tumors acquire new phenotypic features when exposed to anticancer therapy, which helps them endure the struggle for survival and increase malignancy. Using a six-layered multiomic approach, Ma et al. find that selective super-enhancer redistribution is a major driver of the acquisition of new phenotypic features.