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Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer.

ABSTRACT: Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers. SIGNIFICANCE: Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.

SUBMITTER: Shang S

PROVIDER: S-EPMC6744966 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer.

Shang Stephen S Yang Jiekun J Jazaeri Amir A AA Duval Alexander James AJ Tufan Turan T Lopes Fischer Natasha N Benamar Mouadh M Guessous Fadila F Lee Inyoung I Campbell Robert M RM Ebert Philip J PJ Abbas Tarek T Landen Charles N CN Difeo Analisa A Scacheri Peter C PC Adli Mazhar M

Cancer research 20190729 18

Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. ...[more]

PMID: 31358529

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Project description:To understand the chemotherapy response program in ovarian cancer cells at deep transcript sequencing levels.Two next-generation sequencing technologies--MPSS (massively parallel signature sequencing) and SBS (sequencing by synthesis)--were used to sequence the transcripts of IGROV1 and IGROV1-CP cells, and to sequence the transcripts of a highly chemotherapy responsive and a highly chemotherapy resistant ovarian cancer tissue.We identified 3422 signatures (2957 genes) that are significantly different between IGROV1 and IGROV1-CP cells (P<0.001). Gene Ontology (GO) term GO:0001837 (epithelial-to-mesenchymal transition) and GO:0034330 (cell junction assembly and maintenance) are enriched in genes that are over expressed in IGROV1-CP cells while apoptosis-related GO terms are enriched in genes over expressed in IGROV1 cells. We identified 1187 tags (corresponding to 1040 genes) that are differentially expressed between the chemotherapy responsive and the persistently chemotherapy resistant ovarian cancer tissues. GO term GO:0050673 (epithelial cell proliferation) and GO:0050678 (regulation of epithelial cell proliferation) are enriched in the genes over expressed in the chemotherapy resistant tissue while the GO:0007229 (integrin-mediated signaling pathway) is enriched in the genes over expressed in the chemotherapy sensitive tissue. An integrative analysis identified 111 common differentially expressed genes including two bone morphogenetic proteins (BMP4 and BMP7), six solute carrier proteins (SLC10A3, SLC16A3, SLC25A1, SLC35B3, SLC7A5 and SLC7A7), transcription factor POU5F1 (POU class 5 homeobox 1), and KLK10 (kallikrein-related peptidase 10). A network analysis revealed a subnetwork with three genes BMP7, NR2F2 and AP2B1 that were consistently over expressed in the chemoresistant tissue or cells compared to the chemosensitive tissue or cells.Our database offers the first comprehensive view of the digital transcriptomes of ovarian cancer cell lines and tissues with different chemotherapy response phenotypes.

Dataset Information

Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer.

Publications

Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer.

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