CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter
CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter
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DOI：
10.1128/mcb.05869-11
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发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Frasor, Jonna
中科院分区：
文献类型：
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作者：
Pradhan, Madhumita;Baumgarten, Sarah C.;Frasor, Jonna
雌激素受体（ER）和NF-κ B B是对乳腺癌细胞增殖和存活具有深远影响的转录因子。虽然许多研究表明，ER和NF-κ B B可以相互抑制，我们以前确定了一个基因的签名，这是协同上调这两个因素在更积极的管腔B乳腺肿瘤。在此，我们研究了ER和NF-κ B B之间的一种新的串扰机制，该机制导致抗凋亡基因BIRC 3（也称为cIAP 2）的上调。我们证明，NF-κ B B，通过两个反应元件，需要ER招聘到一个相邻的雌激素反应元件（ERE）的BIRC 3启动子。这种效应伴随着ERE周围NE-κ B依赖性组蛋白乙酰化的显著增加。有趣的是，CBP，一种先前参与ER和NF-κ B之间抑制性相互作用的组蛋白乙酰转移酶，通过促进组蛋白乙酰化和ER募集以及增强BIRC 3的表达而发挥允许性作用。这些发现提示了一种新的基因调控机制，炎症和NF-κ B活化可通过这种机制影响ER募集到固有的非活性ER结合位点。这种微调机制可以解释通常抑制彼此活性的两个因素如何在某些基因上共同作用，以促进乳腺癌细胞存活和肿瘤进展。
Estrogen receptor (ER) and NF-kappa B are transcription factors with profound effects on breast cancer cell proliferation and survival. While many studies demonstrate that ER and NF-kappa B can repress each other, we previously identified a gene signature that is synergistically upregulated by these two factors in more aggressive luminal B breast tumors. Herein, we examine a novel mechanism of cross talk between ER and NF-kappa B that results in the upregulation of the antiapoptotic gene BIRC3 (also known as cIAP2). We demonstrate that NF-kappa B, acting through two response elements, is required for ER recruitment to an adjacent estrogen response element (ERE) in the BIRC3 promoter. This effect is accompanied by a major increase in NE-kappa B-dependent histone acetylation around the ERE. Interestingly, CBP, a histone acetyltransferase previously implicated in repressive interactions between ER and NF-kappa B, plays a permissive role by promoting histone acetylation and ER recruitment, as well as enhanced expression of BIRC3. These findings suggest a new gene regulatory mechanism by which inflammation and NF-kappa B activation can influence ER recruitment to inherently inactive ER binding sites. This fine-tuning mechanism may explain how two factors that generally repress each other's activity may work together on certain genes to promote breast cancer cell survival and tumor progression.