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

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dc.contributor.authorAchinger-Kawecka, J.
dc.contributor.authorStirzaker, C.
dc.contributor.authorPortman, N.
dc.contributor.authorCampbell, E.
dc.contributor.authorChia, K.-M.
dc.contributor.authorDu, Q.
dc.contributor.authorLaven-Law, G.
dc.contributor.authorNair, S.S.
dc.contributor.authorYong, A.
dc.contributor.authorWilkinson, A.
dc.contributor.authorClifton, S.
dc.contributor.authorMilioli, H.H.
dc.contributor.authorAlexandrou, S.
dc.contributor.authorCaldon, C.E.
dc.contributor.authorSong, J.
dc.contributor.authorKhoury, A.
dc.contributor.authorMeyer, B.
dc.contributor.authorChen, W.
dc.contributor.authorPidsley, R.
dc.contributor.authorQu, W.
dc.contributor.authoret al.
dc.date.issued2024
dc.descriptionPublished online: 5 January 2024
dc.description.abstractThree-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.
dc.description.statementofresponsibilityJoanna Achinger-Kawecka ... Geraldine Laven-Law ... Theresa E. Hickey ... et al.
dc.identifier.citationNature Structural and Molecular Biology, 2024; 31(3):498-512
dc.identifier.doi10.1038/s41594-023-01181-7
dc.identifier.issn1545-9993
dc.identifier.issn1545-9985
dc.identifier.orcidAchinger-Kawecka, J. [0000-0002-2902-9371]
dc.identifier.orcidLaven-Law, G. [0000-0001-5326-1931]
dc.identifier.orcidHickey, T.E. [0000-0002-2752-730X]
dc.identifier.urihttps://hdl.handle.net/2440/140388
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1063559
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1177792
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2010156
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1128916
dc.rights© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
dc.source.urihttp://dx.doi.org/10.1038/s41594-023-01181-7
dc.subjectChromatin remodelling; Chromatin structure; DNA methylation; Transcriptional regulatory elements
dc.titleThe potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer
dc.typeJournal article
pubs.publication-statusPublished

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