The potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer.
Joanna Achinger-KaweckaClare StirzakerNeil PortmanElyssa CampbellKee-Ming ChiaQian DuGeraldine Laven-LawShalima S NairAliza YongAshleigh WilkinsonSamuel CliftonHeloisa H MilioliSarah AlexandrouC Elizabeth CaldonJenny SongAmanda KhouryBraydon MeyerWenhan ChenRuth PidsleyWenjia QuJulia M W GeeAnthony SchmittEmily S WongTheresa E HickeyElgene LimSusan J ClarkPublished in: Nature structural & molecular biology (2024)
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.
Keyphrases
- dna methylation
- genome wide
- estrogen receptor
- gene expression
- transcription factor
- copy number
- endoplasmic reticulum
- small cell lung cancer
- stem cells
- squamous cell carcinoma
- acute myeloid leukemia
- binding protein
- breast cancer cells
- dna damage
- climate change
- bone marrow
- oxidative stress
- high glucose
- signaling pathway
- risk assessment