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Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [ChIP-seq]

ABSTRACT: Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNF can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically; we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71976 | GEO | 2016/01/20

SECONDARY ACCESSION(S): PRJNA292652

REPOSITORIES: GEO

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Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [microarray]

Project description:Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNFalpha can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically, we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response. BT549 cells were cultured to 50% confluency and transfected with control or c-Jun siRNA for 72 hours, followed by treatment with or without TNFÎ± for 6 hours.

2016-01-20 | E-GEOD-71915 | biostudies-arrayexpress

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [microarray]

2016-01-20 | GSE71915 | GEO

Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (expression)

Project description:Triple negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We find that the AP-1 transcription factor component, Fra-1, is overexpressed in basal-like breast tumors, and its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes in TNBC cells. To gain insights into the transcriptional regulatory networks of AP-1 in TNBC cells, we combine genome-wide ChIP-seq with loss-of-function transcriptome analyses. We observe dysregulation of direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Intriguingly, we find that AP-1 mediates downregulation of E-cadherin through direct transcriptional induction of ZEB2. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and proliferative propensity. BT549 cells grown in complete medium were transfected with a control siRNA, siRNA targeting Fra-1 or siRNA targeting c-Jun for 72 h, and then global gene expression profiles were assessed. Three or four biological replicates were used for each group.

2014-06-30 | E-GEOD-46440 | biostudies-arrayexpress

Genomic expression profiling of TNFalpha treated BDC2.5 diabetogenic CD4+ T Cells

Project description:Tumor necrosis factor alpha (TNFalpha) plays an important role in immune regulation, inflammation, and autoimmunity. Chronic TNFalpha exposure has been shown to down-modulate T cell responses. In a mouse T cell hybridoma model, TNFalpha attenuated T cell receptor (TCR) signaling. We have confirmed that chronic TNFalpha and anti-TNFalpha exposure suppressed and increased T cell responses in BDC2.5 CD4+ T cells, respectively. The goal of this study is to analyze global transcriptional alterations resulting from TNFalpha treatment on TCR signaling pathways using cDNA microarrays. We found that genes involved in functional categories including T cell signaling, cell cycle, proliferation, ubiquitination, cytokine synthesis, calcium signaling, and apoptosis were modulated. Genes such as ubiquitin family genes, cytokine inducible SH2-containing genes, cyclin-dependent kinase inhibitors p21, p57, calmodulin family genes (calmodulin -V1, -V2, and ?V3) and calcium channel voltage- dependent, N type alpha1B subunit (CaV2.2) were induced by TNFalpha, while Vav2, Rho GTPase activating protein, calcium channel voltage dependent, L type alpha 1C subunit (CaV1.2), interleukin-1 (IL) receptor-associated kinase 1, and -V2 (IRAK-1and -2) and IL enhancer binding factor 3 were reduced by TNFalpha. Genes such as CaV1.2 and proliferating cell nuclear antigen, repressed by TNFalpha, were induced by anti-TNF treatment. Further, we showed that chronic TNFalpha exposure impaired NF-kappaB and AP-1 transactivation activity, leading to T cell unresponsiveness. Thus, our results present a detailed picture of transcriptional programs affected by chronic TNFalpha exposure, and provide candidate target genes, which may function to mediate TNFalpha induced T cell unresponsiveness. Set of arrays that are part of repeated experiments Keywords: Biological Replicate

2008-07-01 | GSE10029 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression.

Project description:Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression.

| PRJNA292649 | ENA

Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (expression)

2014-06-30 | GSE46440 | GEO

Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (ChIP-seq)

2014-06-30 | GSE46166 | GEO

Microarray analysis of the regulation of TNFalpha-stimulated PGE2 production in gingival fibroblasts

Project description:Prostaglandin E2 (PGE2) is involved in several inflammatory conditions including periodontitis. The aim of this study was to investigate the global gene expression profile of tumor necrosis factor alpha (TNFalpha) stimulated human gingival fibroblasts, focusing on signal pathways related to PGE2 production and the new PGE2-synthesizing enzymes, prostaglandin E synthases (PGES). The expression of microsomal prostaglandin E synthase-1 (mPGES-1) as well as the upstream cyclooxygenase-2 (COX-2) was up-regulated by TNFalpha, accompanied by increased PGE2 production. In contrast, the expression of microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFalpha. Using microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, we identified differentially expressed genes in response to TNFalpha treatment. Enrichment analysis of microarray data identified two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappaB (NF-kappaB). We used specific inhibitors and phosphorylation analysis to confirm their role in PGE2 regulation. Both JNK and NF-kappaB inhibitors reduced the TNFalpha-stimulated up-regulation of mPGES-1 and COX-2 as well as subsequent PGE2 production. The novel finding that TNFalpha-stimulated mPGES-1 is regulated by JNK suggests this kinase as a potential future target for treatment strategies in inflammatory disorders, including periodontitis. Keywords: Time course, gene expression, factorial design.

2008-12-11 | GSE13903 | GEO

Role for AP-1 transcription factors (c-Jun, c-Fos) in prostate cancer progression and clinical outcome of prostate tumor

Project description:In our investigations of the molecular pathways of prostate tumorigenesis in Nkx3.1; Pten mutant mice using gene expression profiling, we now find that the AP-1 transcription factors, c-Jun and c-Fos, are significantly up-regulated during cancer progression. Forced expression of c-Fos and c-Jun in prostate cancer cells results in increased tumorigenicity, activation of Erk MAP kinase, and enhanced survival in the absence of androgens, which are hallmarks of disease progression. In humans, Jun and Fos proteins are significantly up-regulated during prostate cancer progression and significantly correlated with activation of Erk MAP kinase. Most notably, expression of Jun is associated with disease recurrence independent of other currently used prognostic indicators. These analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression vis-à-vis Erk MAP kinase signaling, as well as the identification of a novel marker of disease recurrence, namely c-Jun. Keywords: Stages of Prostate Cancer

2008-06-27 | GSE11836 | GEO

Histone modification analysis in TGFbeta/TNFalpha treated A549 spheroid cultures

Project description:We studied the extent of chromatin remodeling in an in-vitro model of the epithelial-mesenchymal transition (EMT). EMT is induced in spheroid cultures (3D) using simultaneously two cytokines: TGFbeta and TNFalpha. The epithelial-mesenchymal transition (EMT) is a cellular de-differentiation process that has been implicated in cancer progression and metastasis. Increasing evidence suggests that EMT is regulated and established by epigenetic reprogramming, however a systems-level mechanism describing how chromatin remodeling contributes to the phenotypic switch is not known. We have generated genome-wide maps of 18 histone modifications/variants and variants in both the epithelial and mesenchymal states and quantified patterns of epigenetic changes at gene and enhancer loci. Clusters of these patterns reveal that EMT-related genes and their proximal enhancers are regulated through coordinated patterns of chromatin activation and repression at both gene and enhancer loci. At the cellular level, the remodeling of gene loci translates into a modular protein interaction network that recapitulates EMT-related signaling. Moreover, differentially activated or repressed enhancers are associated with two non-overlapping sets of transcription factors. We propose a chromatin-mediated regulatory feedback loop model where the NFkappaB and AP-1 transcription factors (TFs) bind activated enhancers, that regulate EMT-related genes, which in turn activate signaling pathways upstream of these TFs.

2013-09-12 | E-GEOD-42374 | biostudies-arrayexpress

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