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ABSTRACT Multiple DNA methylation changes in the cancer methylome are associated with the acquisition of drug resistance; however it remains uncertain how many represent critical DNA

methylation drivers of chemoresistance. Using isogenic, cisplatin-sensitive/resistant ovarian cancer cell lines and inducing resensitizaton with demethylating agents, we aimed to identify

consistent methylation and expression changes associated with chemoresistance. Using genome-wide DNA methylation profiling across 27 578 CpG sites, we identified loci at 4092 genes becoming

hypermethylated in chemoresistant A2780/cp70 compared with the parental-sensitive A2780 cell line. Hypermethylation at gene promoter regions is often associated with transcriptional

silencing; however, expression of only 245 of these hypermethylated genes becomes downregulated in A2780/cp70 as measured by microarray expression profiling. Treatment of A2780/cp70 with the

demethylating agent 2-deoxy-5′-azacytidine induces resensitization to cisplatin and re-expression of 41 of the downregulated genes. A total of 13/41 genes were consistently hypermethylated

in further independent cisplatin-resistant A2780 cell derivatives. CpG sites at 9 of the 13 genes (_ARHGDIB_, _ARMCX2_, _COL1A, FLNA_, _FLNC_, _MEST_, _MLH1_, _NTS_ and _PSMB9_) acquired

methylation in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 genes (_ARMCX2_, _COL1A1_, _MDK_,

_MEST_ and _MLH1_) acquired methylation in drug-resistant ovarian cancer-sustaining (side population) cells. MLH1 has a direct role in conferring cisplatin sensitivity when reintroduced into

cells _in vitro_. This combined genomics approach has identified further potential key drivers of chemoresistance whose expression is silenced by DNA methylation that should be further

evaluated as clinical biomarkers of drug resistance. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS GENOME-WIDE DNA METHYLATION ANALYSIS OF KRAS MUTANT CELL LINES Article Open

access 23 June 2020 THE DNA METHYLATION LANDSCAPE OF ADVANCED PROSTATE CANCER Article 13 July 2020 EPIGENOME-WIDE ANALYSIS REVEALS FUNCTIONAL MODULATORS OF DRUG SENSITIVITY AND

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adducts. _Mol Cell_ 22: 501–510. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Lisa McMillan for her valuable contribution to the initial analysis of the

Affymetrix expression data. We also thank Nahal Masrour for preparation of samples and Kerra Pearce for running the Infinium HumanMethylation450 BeadChips at the UCL Genomics Center, London.

This work was supported by a Cancer Research UK (CZ, WD and RB) grant (C536/A6689), Imperial Experimental Cancer Medicine Centre, Imperial Biomedical Research Centre and Ovarian Cancer

Action (SR and CSMWB). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Surgery and Cancer, Epigenetics Unit, Imperial College London, London, UK C Zeller, W Dai, C S M

Wilhelm-Benartzi & R Brown * Beatson West of Scotland Cancer Centre, Glasgow, UK N L Steele * Department of Genomics of Common Disease, School of Public Health, Hammersmith Hospital,

London, UK A Siddiq & A J Walley * Section of Medicine, Institute of Cancer Research, Sutton, UK S Rizzo & R Brown * Department of Obstetrics and Gynecology, University Medical

Center Groningen, University of Groningen, Groningen, The Netherlands A van der Zee * Cancer Research UK Beatson Laboratories, Institute of Cancer Sciences, University of Glasgow, Glasgow,

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ARTICLE Zeller, C., Dai, W., Steele, N. _et al._ Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling.

_Oncogene_ 31, 4567–4576 (2012). https://doi.org/10.1038/onc.2011.611 Download citation * Received: 23 May 2011 * Revised: 29 October 2011 * Accepted: 28 November 2011 * Published: 16

January 2012 * Issue Date: 18 October 2012 * DOI: https://doi.org/10.1038/onc.2011.611 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * drug

resistance * cisplatin * DNA methylation * ovarian cancer * DNMTi * HDACi