Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells.
Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells.
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DOI：
10.1038/onc.2009.323
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发表时间：
2010-01-14
期刊：
影响因子：
8
通讯作者：
Miele L
中科院分区：
文献类型：
--
作者：
Hao L;Rizzo P;Osipo C;Pannuti A;Wyatt D;Cheung LW;Sonenshein G;Osborne BA;Miele L
大约80%的乳腺癌表达雌激素受体-α（ERα），并使用抗雌激素治疗。对这些药剂的耐药性是死亡的主要原因。我们已经表明，雌激素抑制Notch，而抗雌激素或雌激素戒断激活Notch信号。联合抑制Notch和雌激素信号在ERα阳性乳腺癌模型中具有协同效应。然而，Notch-1促进ERα阳性乳腺癌细胞生长的机制尚不清楚。在这里，我们证明了Notch-1通过一种新的染色质串扰机制在雌激素存在或不存在的情况下增加ERα应答基因的转录。我们的数据支持一个模型，其中Notch-1可以通过Notch-CSL-MAML 1转录复合物（NTC）和ERα的IKKα依赖性合作染色质募集来激活ERα靶基因的转录，这促进了p300的募集。CSL结合元件经常出现在人类和小鼠基因组中的雌激素反应元件（ERE）附近。我们的观察结果表明，迄今为止未知的Notch-1/ERα染色质串扰介导ERα阳性乳腺癌细胞中的Notch信号传导效应，并有助于调节ERα本身的转录功能。
Approximately 80% of breast cancers express the estrogen receptor-α (ERα) and are treated with anti-estrogens. Resistance to these agents is a major cause of mortality. We have shown that estrogen inhibits Notch, whereas anti-estrogens or estrogen withdrawal activate Notch signaling. Combined inhibition of Notch and estrogen signaling has synergistic effects in ERα-positive breast cancer models. However, the mechanisms whereby Notch-1 promotes the growth of ERα-positive breast cancer cells are unknown. Here, we demonstrate that Notch-1 increases the transcription of ERα-responsive genes in the presence or absence of estrogen via a novel chromatin crosstalk mechanism. Our data support a model in which Notch-1 can activate the transcription of ERα-target genes via IKKα-dependent cooperative chromatin recruitment of Notch–CSL–MAML1 transcriptional complexes (NTC) and ERα, which promotes the recruitment of p300. CSL binding elements frequently occur in close proximity to estrogen-responsive elements (EREs) in the human and mouse genomes. Our observations suggest that a hitherto unknown Notch-1/ERα chromatin crosstalk mediates Notch signaling effects in ERα-positive breast cancer cells and contributes to regulate the transcriptional functions of ERα itself.