Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, 860-0811, Japan.
Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt.
Nat Commun. 2019 Aug 22;10(1):3778. doi: 10.1038/s41467-019-11378-4.
MCF7 cells acquire estrogen-independent proliferation after long-term estrogen deprivation (LTED), which recapitulates endocrine therapy resistance. LTED cells can become primed for apoptosis, but the underlying mechanism is largely unknown. We previously reported that Eleanor non-coding RNAs (ncRNAs) upregulate the ESR1 gene in LTED cells. Here, we show that Eleanors delineate the topologically associating domain (TAD) of the ESR1 locus in the active nuclear compartment of LTED cells. The TAD interacts with another transcriptionally active TAD, which is 42.9 Mb away from ESR1 and contains a gene encoding the apoptotic transcription factor FOXO3. Inhibition of a promoter-associated Eleanor suppresses all genes inside the Eleanor TAD and the long-range interaction between the two TADs, but keeps FOXO3 active to facilitate apoptosis in LTED cells. These data indicate a role of ncRNAs in chromatin domain regulation, which may underlie the apoptosis-prone nature of therapy-resistant breast cancer cells and could be good therapeutic targets.
MCF7 细胞在长期去雌激素剥夺（LTED）后获得雌激素非依赖性增殖，从而重现内分泌治疗耐药性。LTED 细胞可以被诱导凋亡，但潜在的机制在很大程度上尚不清楚。我们之前报道过 Eleanor 非编码 RNA（ncRNA）上调 LTED 细胞中的 ESR1 基因。在这里，我们表明 Eleanor 划定了 LTED 细胞中 ESR1 基因座的拓扑关联结构域（TAD）。该 TAD 与另一个转录活性的 TAD 相互作用，该 TAD 距离 ESR1 有 42.9Mb 远，包含编码凋亡转录因子 FOXO3 的基因。与启动子相关的 Eleanor 的抑制作用抑制了 Eleanor TAD 内的所有基因和两个 TAD 之间的长程相互作用，但保持 FOXO3 活性以促进 LTED 细胞凋亡。这些数据表明 ncRNA 在染色质结构域调节中起作用，这可能是治疗耐药性乳腺癌细胞易凋亡的基础，并且可能是良好的治疗靶点。
