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Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer Stephen Shang1, Jiekun Yang1, Amir A

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Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer Stephen Shang1, Jiekun Yang1, Amir A Published OnlineFirst July 29, 2019; DOI: 10.1158/0008-5472.CAN-19-0215 Cancer Genome and Epigenome Research Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer Stephen Shang1, Jiekun Yang1, Amir A. Jazaeri2, Alexander James Duval1, Turan Tufan1, Natasha Lopes Fischer1, Mouadh Benamar1,3, Fadila Guessous3, Inyoung Lee1, Robert M. Campbell4, Philip J. Ebert4, Tarek Abbas1,3, Charles N. Landen5, Analisa Difeo6, Peter C. Scacheri6, and Mazhar Adli1 Abstract Chemoresistance is driven by unique regulatory net- tance, our findings identified SOX9 as a critical SE-regulated works in the genome that are distinct from those necessary transcription factor that plays a critical role in acquiring for cancer development. Here, we investigate the contri- and maintaining the chemoresistant state in ovarian cancer. bution of enhancer elements to cisplatin resistance in The approach and findings presented here suggest that ovarian cancers. Epigenome profiling of multiple cellular integrative analysis of epigenome and transcriptional pro- models of chemoresistance identified unique sets of distal grams could identify targetable key drivers of chemoresis- enhancers, super-enhancers (SE), and their gene targets tance in cancers. that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharma- Significance: Integrative genome-wide epigenomic and cologic inhibition of distal enhancers through small- transcriptomic analyses of platinum-sensitive and -resistant molecule epigenetic inhibitors suppressed the expression ovarian lines identify key distal regulatory regions and of their target genes and restored cisplatin sensitivity in vitro associated master regulator transcription factors that can be and in vivo. In addition to known drivers of chemoresis- targeted by small-molecule epigenetic inhibitors. Introduction epithelial ovarian cancer are high-grade serous ovarian cancer (HGSOC; ref. 7) that are more challenging to effectively treat. The The American Cancer Society estimates 22,240 new cases of first-line therapy for ovarian cancer involves the combination of ovarian cancer in 2018 (1). Unfortunately, the five-year survival cytoreductive surgery followed by platinum and taxane-based rate of ovarian cancer remains less than 50%. Thus, nearly 14,000 chemotherapy. Platinum-based compounds such as cisplatin women in the United States and 160,000 worldwide die of induce increased DNA damage through interstrand cross-links ovarian cancer each year (2). Epithelial ovarian cancers, which and cell death in proliferative cancerous cells (7, 8). Despite the account for nearly 90% of all ovarian cancer diagnoses, are high rate of initial response to therapy, the duration of response associated with worse prognosis (3). They originate mainly from declines over time and a vast majority of patients succumb to the epithelial cells of fallopian tubes (4, 5) and areas of endo- chemotherapy-resistant ovarian cancer (9–12). metriosis (6), among others. Critically, 75% of the patients with Recent genomic approaches have shed significant light on the genetic risk factors of ovarian cancer. Low-grade ovarian tumors 1 often harbor BRAF, KRAS, BRCA1/2, and PTEN mutations, where- Department of Biochemistry and Molecular Genetics, University of Virginia TP53 School of Medicine, Charlottesville, Virginia. 2Department of Gynecologic Oncol- as high-grade tumors are uniformly characterized by muta- ogy and Reproductive Medicine, The University of Texas MD Anderson Cancer tions (13, 14). Apart from the antiangiogenic agent bevacizumab, Center, Houston, Texas. 3Department of Radiation Oncology, University of and partially effective PARP inhibitors for patients with BRCA1/2 Virginia, Charlottesville, Virginia. 4Lilly Research Laboratories, Eli Lilly and mutations (15), targeted therapies are lacking for ovarian cancer. 5 Company, Indianapolis, Indiana. Department of Obstetrics and Gynecology, Although specific genetic alterations such as reversion of germline University of Virginia School of Medicine, Charlottesville, Virginia. 6Department BRCA1/2 mutations and inactivating mutations in tumor sup- of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case RB1, NF1, RAD51B, PTEN Western Reserve University, Cleveland, Ohio. pressor and genes were noted in some chemoresistant patients (16), the molecular network that drives Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). and maintains the chemoresistant state in ovarian cancer is largely unknown. In addition to genetic alterations, epigenetic regulation Corresponding Author: Mazhar Adli, Department of Biochemistry and Molecular of proximal promoters and distal enhancers are critical determi- Genetics, University of Virginia School of Medicine, 1340 JPA, Pinn Hall, Rm 6240, Charlottesville, VA 22902. E-mail: [email protected] nants of cellular identities. Alterations in the chromatin landscape are increasingly recognized as hallmarks of malignant cellular Cancer Res 2019;79:1–13 states (17–19). Because of the technical limitations, previous doi: 10.1158/0008-5472.CAN-19-0215 ovarian cancer epigenetic studies primarily focused on targeted Ó2019 American Association for Cancer Research. DNA methylation at individual gene promoters. Although these www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 29, 2019; DOI: 10.1158/0008-5472.CAN-19-0215 Shang et al. studies implicate differential methylation at multiple genes, such on the viability levels. Once the cells gain resistance, either the as MLH1 (20), SFRP1 (21), BRCA1 (16), MAL (22), FANCF (23) dose was increased or cells were periodically treated with with chemoresistance, there have been limited attempts to com- cisplatin to maintain the chemoresistant state. Resistant prehensively map differentially regulated gene promoters and SKOV3 cells reached a maximum concentration of 20 mmol/L distal enhancers in ovarian cancer. cisplatin tolerance, OV81 cells reached a maximum concentra- In this study, we aimed to identify molecular drivers of che- tion of 40 mmol/L, OVCAR3 cells reached a maximum periodic moresistance in ovarian cancer through unbiased epigenomic and dose of 18 mmol/L cisplatin, and OVCAR4 cells' largest sus- transcriptional profiling across multiple cellular models of ovar- tainable periodic dose of cisplatin was 12 mmol/L. ian cancer. We aimed to map differentially regulated proximal promoters and distal enhancers in multiple cellular models MTT and crystal violet cell proliferation and viability assay of ovarian cancer. By integrating genome-wide maps of a well- Each cell line was seeded at a density of 4–6 Â 102 cells/well in characterized epigenetic mark of active regulatory genomic flat-bottomed 96-well culture plate in 100 mL of the culture elements with gene expression profiles, we aimed to identify medium. Stock solutions of cisplatin were subjected to serial differentially regulated proximal promoters and distal regulatory dilutions to give final concentrations ranging from 0.1 mmol/L elements that are specifically associated with chemoresistance to 250 mmol/L. JQ1 stock suspended in DMSO was first diluted to across multiple ovarian cancer cell lines. To this end, we generated 10Â of the final concentration in DMSO, then further diluted multiple isogenic cellular models of cisplatin resistance and per- in PBS or complete media to concentrations of 0.25 to 2 mmol/L. formed chromatin immunoprecipitation sequencing (ChIP-seq) The dilutions were added to equal volumes of cell culture in analysis of the histone H3, lysine 27 acetylation (H3K27ac) triplicate wells and then the cells were left to incubate. After epigenetic mark, which is deposited to active enhancers and 24 hours, the media were aspirated and then washed once with promoters. By integrating ChIP-seq maps with RNA-seq gene 1 volume of PBS, then replaced with 1 volume of the cell's expression profiles across na€ve and chemoresistant cellular coun- respective complete media and left to incubate. After 48 hours, terparts, we found that the chemoresistant state is associated with 10% well volume of stock MTT diluted to 5 mg/mL was added largely cell-type–specific sets of distal enhancer elements. Criti- to 100–150 mL of fresh complete media, then added to each cally, we found significant upregulation of distal enhancer clusters well after aspirating the previous media. After 3–4 hours of known as super-enhancers (SE) in resistant cells. Small-molecule incubation, 1 equal volume of MTT solubilization media epigenetic drugs that target enhancers and SEs result in significant (10% SDS, 0.1% Tris HCl) was added to each well, then covered, decrease in the expression of their target genes and an increase in and stored at room temperature or in the incubator for 7þ hours. cisplatin sensitivity in chemoresistant HGSOC cells. Our findings The plate was read on a plate reader that shakes the plate, then identified, in addition to known drivers of chemoresistance, reads absorbance at 590 nmol/L. Background absorbance was SOX9 as a critical SE-regulated transcription factor (TF) that plays taken to be the readings of control wells with no cells. These a critical role in chemoresistance across multiple ovarian cancer treatments were carried out to determine IC50 values, that is, drug cell lines. concentrations required
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