Long non-coding RNA (lncRNA)−mediated control of gene expression contributes to regulation of biological processes that include proliferation and phenotype, as well as compromised expression of genes that are functionally linked to cancer initiation and tumor progression. lncRNAs have emerged as novel targets and biomarkers in breast cancer. We have shown that mitotically associated lncRNA MANCR is expressed in triple-negative breast cancer (TNBC) cells and that it serves a critical role in promoting genome stability and survival in aggressive breast cancer cells. Using an siRNA strategy, we selectively depleted BRD2, BRD3, and BRD4, singly and in combination, to establish which bromodomain proteins regulate MANCR expression in TNBC cells. Our findings were confirmed by using in situ hybridization combined with immunofluorescence analysis that revealed BRD4, either alone or with BRD2 and BRD3, can support MANCR regulation of TNBC cells. Here we provide evidence for MANCR-responsive epigenetic control of super enhancers by histone modifications that are required for gene transcription to support cell survival and expression of the epithelial tumor phenotype in triple negative breast cancer cells.

中文翻译：

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Bromodomain 蛋白表观遗传调节三阴性乳腺癌细胞中的有丝分裂相关 lncRNA MANCR

长非编码RNA（lncRNA）介导的基因表达控制有助于调节生物过程，包括增殖和表型，以及与癌症发生和肿瘤进展功能相关的基因表达受损。lncRNA 已成为乳腺癌的新靶点和生物标志物。我们已经证明，有丝分裂相关的lncRNA MANCR在三阴性乳腺癌（TNBC）细胞中表达，并且它在促进侵袭性乳腺癌细胞的基因组稳定性和存活方面发挥着关键作用。使用 siRNA 策略，我们选择性地单独或组合地去除 BRD2、BRD3 和 BRD4，以确定哪些溴结构域蛋白调节 TNBC 细胞中的 MANCR 表达。我们的研究结果通过原位杂交结合免疫荧光分析得到证实，显示 BRD4 单独或与 BRD2 和 BRD3 一起，可以支持 TNBC 细胞的 MANCR 调节。在这里，我们提供了通过组蛋白修饰对超级增强子进行 MANCR 反应性表观遗传控制的证据，这些组蛋白修饰是基因转录所需的，以支持三阴性乳腺癌细胞中的细胞存活和上皮肿瘤表型的表达。