The potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer

Achinger-Kawecka, Joanna, Stirzaker, Clare, Portman, Neil, Campbell, Elyssa, Chia, Kee-Ming, Du, Qian, Laven-Law, Geraldine, Nair, Shalima S., Yong, Aliza, Wilkinson, Ashleigh, Clifton, Samuel, Milioli, Heloisa H., Alexandrou, Sarah, Caldon, C. Elizabeth, Song, Jenny, Khoury, Amanda, Meyer, Braydon, Chen, Wenhan, Pidsley, Ruth, Qu, Wenjia, Gee, Julia M. W. ORCID: https://orcid.org/0000-0001-6483-2015, Schmitt, Anthony, Wong, Emily S., Hickey, Theresa E., Lim, Elgene and Clark, Susan J. 2024. The potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer. Nature Structural and Molecular Biology 31 , pp. 498-512. 10.1038/s41594-023-01181-7

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Abstract

Three-dimensional (3D) epigenome remodeling is an important mechanism of gene deregulation in cancer. However, its potential as a target to counteract therapy resistance remains largely unaddressed. Here, we show that epigenetic therapy with decitabine (5-Aza-mC) suppresses tumor growth in xenograft models of pre-clinical metastatic estrogen receptor positive (ER+) breast tumor. Decitabine-induced genome-wide DNA hypomethylation results in large-scale 3D epigenome deregulation, including de-compaction of higher-order chromatin structure and loss of boundary insulation of topologically associated domains. Significant DNA hypomethylation associates with ectopic activation of ER-enhancers, gain in ER binding, creation of new 3D enhancer–promoter interactions and concordant up-regulation of ER-mediated transcription pathways. Importantly, long-term withdrawal of epigenetic therapy partially restores methylation at ER-enhancer elements, resulting in a loss of ectopic 3D enhancer–promoter interactions and associated gene repression. Our study illustrates the potential of epigenetic therapy to target ER+ endocrine-resistant breast cancer by DNA methylation-dependent rewiring of 3D chromatin interactions, which are associated with the suppression of tumor growth.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	Nature Research
ISSN:	1545-9993
Date of First Compliant Deposit:	16 February 2024
Date of Acceptance:	15 November 2023
Last Modified:	15 Apr 2024 14:43
URI:	https://orca.cardiff.ac.uk/id/eprint/166367

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