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H2A.Z overexpression promotes cellular proliferation of breast cancer cells.

机译:H2A.Z过表达促进乳腺癌细胞的细胞增殖。

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We recently showed that histone H2A.Z, as well as members of the ATP-dependent p400 chromatin remodeling complex (p400.com), are essential components of estrogen receptor alpha (ERalpha) signaling. More specifically, we showed that H2A.Z and p400.com are incorporated into the promoter regions of ERalpha target genes only upon gene induction, and also in a cyclic fashion. RNAi-mediated cellular depletion of H2A.Z and p400.com strongly impedes estrogen-dependent growth of breast cancer cells as well as strongly affect ERalpha-target gene expression. Two mechanisms emerged from our studies of how H2A.Z incorporation within ERalpha-target regulatory regions can actually regulate estrogen-mediated signaling: (1) by stabilizing nucleosomes within the translational DNA axis, a process that allows general transcription factors to be efficiently recruited to promoter regions; (2) by allowing estrogen-responsive enhancer function. In the current study, we now show that in MCF7 cells, ectopic overexpression of H2A.Z increases proliferation, and such in conditions where estrogen levels are low. Also, immunohistochemical studies of breast cancer biopsies show that the presence of H2A.Z correlates highly with that of ERalpha, but is associated with high-grade ER-negative cancers. Finally we show that ERalpha directly associates to the H2A.Z promoter, and consequently modulates its expression. Our study provides a possible link between H2A.Z and endocrine resistance by showing that H2A.Z overexpression leads to increased growth, particularly when estrogen levels are very low.
机译:我们最近显示,组蛋白H2A.Z以及ATP依赖的p400染色质重塑复合体(p400.com)的成员是雌激素受体α(ERalpha)信号传导的重要组成部分。更具体地,我们表明H2A.Z和p400.com仅在基因诱导时并且还以循环方式掺入到ERalpha目标基因的启动子区域。 RNAi介导的H2A.Z和p400.com的细胞耗竭强烈阻碍了雌激素依赖性乳腺癌细胞的生长,并强烈影响了ERalpha靶基因的表达。我们关于在H2A.Z掺入ERalpha-靶标调控区内如何实际调控雌激素介导的信号传导的研究出现了两种机制:(1)通过稳定翻译DNA轴内的核小体,这一过程可以有效地招募一般转录因子,启动子区域; (2)通过允许雌激素反应的增强剂功能。在当前的研究中,我们现在显示在MCF7细胞中,H2A.Z的异位过表达会增加增殖,在雌激素水平较低的情况下也是如此。此外,乳腺癌活检的免疫组织化学研究表明,H2A.Z的存在与ERalpha高度相关,但与高度ER阴性的癌症相关。最后,我们表明ERalpha直接关联到H2A.Z启动子,并因此调节其表达。我们的研究通过显示H2A.Z过表达导致生长增加,尤其是在雌激素水平非常低的情况下,提供了H2A.Z与内分泌耐药性之间的可能联系。

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