Epigenetic therapy suppresses endocrine-resistant breast tumour growth by re-wiring ER-mediated 3D chromatin interactions

Three-dimensional (3D) epigenome remodelling is emerging as an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome cancer therapy resistance remains largely unaddressed. Here we show that treatment of endocrine-resistant estrogen receptor positive (ER+) breast cancer with an FDA-approved epigenetic therapy Decitabine (5-Aza-mC), results in genome-wide DNA hypomethylation and suppression of tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Systematic integration of matched chromatin conformation capture (Hi-C), Promoter Capture Hi-C, RNA-seq and ER ChIP-seq data revealed widespread effects on epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associating domains (TAD) boundary insulation. Key enhancer ER binding sites were demethylated and re-activated after Decitabine treatment, resulting in new ER-mediated enhancer-promoter interactions and concordant activation of tumour-suppressive gene pathways. Importantly, we show that the activated ER target genes were also predictive of good outcome in multiple ER+ breast cancer clinical cohorts. Together our study reveals a previously undescribed mechanism of Decitabine in re-wiring DNA methylation-dependent 3D genome architecture resulting in suppression of tumour growth, and highlights the potential of epigenetic therapy in targeting ER+ endocrine-resistant breast cancer. One line summary Epigenetic therapy suppresses tumour growth in metastatic ER+ breast cancer via DNA hypomethylation-induced rewiring of long-range ER-mediated enhancer-promoter chromatin interactions to activate ER target genes involved in repression of proliferation and the cell cycle. ### Competing Interest Statement A.S. is an employee of Arima Genomics, Inc. Other authors declare no competing interests.