CBP Mediates NF-κB-Dependent Histone Acetylation and Estrogen Receptor Recruitment to an Estrogen Response Element in the BIRC3 Promoter

Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 11/2011; 32(2):569-75. DOI: 10.1128/MCB.05869-11
Source: PubMed


Estrogen receptor (ER) and NF-κB are transcription factors with profound effects on breast cancer cell proliferation and survival.
While many studies demonstrate that ER and NF-κB 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-κB that results in the upregulation of the antiapoptotic gene BIRC3 (also known as cIAP2). We demonstrate that NF-κB, 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 NF-κB-dependent histone acetylation around the ERE. Interestingly,
CBP, a histone acetyltransferase previously implicated in repressive interactions between ER and NF-κB, 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-κB 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.

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    • "Another prominent EMT-related transcription factor, Snail, has also been implicated in ER suppression and endocrine resistance (Dhasarathy et al. 2007). Other internal cellular factors include acquired intracellular alterations in kinase signalling pathways (Brodie et al. 2005, Massarweh et al. 2006, Creighton et al. 2010, Giamas et al. 2011), trans-repression through upregulation of NFkB (Pradhan et al. 2012, Sas et al. 2012), effects of proteasome targeting factors (Man & Zhang 2011, Pan et al. 2011) or microRNA expression (Guttilla et al. 2012). Finally, suppression of ESR1 can also be caused by various extracellular factors including growth factors and cytokines (to be discussed below). "
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    ABSTRACT: It is increasingly clear that inflammation-associated mechanisms can affect breast cancer progression and modulate response to treatment. Estrogen receptor alpha (ERα) is the principal biomarker and therapeutic target for endocrine therapies in breast cancer. Over 70% of patients are ERα positive at diagnosis and are candidates for endocrine therapy. However, ERα positive tumors can become resistant to endocrine therapy. Multiple mechanisms of endocrine resistance have been proposed including ERα suppression. This review discusses the relationship between intratumoral inflammation and endocrine resistance with a particular focus on inflammation-mediated suppression of ERα.
    Full-text · Article · Nov 2014 · Endocrine Related Cancer
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    • "This may contribute to kidney disease progression. BIRC3 plays an important role in promoting estrogen dependent breast cancer cell survival and protecting against TNFα-induced cell death (30). The nature of the BIRC3 estrogen response element is nearly identical to a consensus sequence, and conversion to a perfect consensus sequence does not significantly increase estrogen receptor activity, suggesting that another factor may be preventing estrogen receptor from interacting with this binding site. "
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    ABSTRACT: Membranous nephropathy (MN), characterized by the presence of diffuse thickening of the glomerular basement membrane and subepithelial in situ immune complex disposition, is the most common cause of idiopathic nephrotic syndrome in adults, with an incidence of 5-10 per million per year. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of human MN, but the specific biomarkers of MN have not been fully elucidated. As a result, our knowledge of the alterations in histone methylation in MN is unclear. We used chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to analyze the variations in a methylated histone (H3K9me3) in peripheral blood mononuclear cells from 10 MN patients and 10 healthy subjects. There were 108 genes with significantly different expression in the MN patients compared with the normal controls. In MN patients, significantly increased activity was seen in 75 H3K9me3 genes, and decreased activity was seen in 33, compared with healthy subjects. Five positive genes, DiGeorge syndrome critical region gene 6 (DGCR6), sorting nexin 16 (SNX16), contactin 4 (CNTN4), baculoviral IAP repeat containing 3 (BIRC3), and baculoviral IAP repeat containing 2 (BIRC2), were selected and quantified. There were alterations of H3K9me3 in MN patients. These may be candidates to help explain pathogenesis in MN patients. Such novel findings show that H3K9me3 may be a potential biomarker or promising target for epigenetic-based MN therapies.
    Full-text · Article · Dec 2013 · Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]
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    • "has also been shown that NF - jB can suppress ERa activity in several exper - imental models ( Bodine et al . , 1999 ; Feldman et al . , 2007 ; Wang et al . , 2009 ) . NF - jB and ERa can also synergistically induce expres - sion of target genes which are involved in inflammation ( Frasor et al . , 2008 ) , apoptosis ( Stanculescu et al . , 2010 ; Pradhan et al . , 2012 ) , proliferation ( Tu et al . , 2006 ) and drug - resistance ( Pradhan et al . , 2010 ) . These studies in total suggest that NF - jB activation by a proinflammatory tumor microenvironment can promote an aggressive breast cancer phenotype through activating or sup - pressing ERa target gene expression in a context - dependent man - ner"
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    ABSTRACT: During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ER α)-dependent and ER α -independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ER α positive breast cancers.
    Full-text · Article · Jun 2013 · Molecular and Cellular Endocrinology
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