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Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1 [RNA-seq]

ABSTRACT: Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor progression. However, a systematic analysis of the composition of the Fra-1 protein network specifically on chromatin is still missing. Here we performed endogenous purification of Fra-1 transcriptional complex under ChIP conditions, followed by mass spectrometry, to identify chromatin-bound partners of Fra-1 in TNBC cells. This study allowed the identification of 118 interactors, highlighting DDX5 as the high ranking of Fra-1 interacting proteins. DDX5, a previously unrecognized protein in the network, is recruited globally to Fra-1 binding sites and shares a substantial set of Fra-1 target genes required for the TNBC cell growth. We provide evidence that DDX5 expression enhances Fra-1 transcriptional activity, thereby enhancing Fra-1-driven tumorigenesis. By integrating ChIP-seq and RNA-seq, we show that DDX5 target gene signature predicts poor clinical outcome in breast cancer patients. DDX5 protein level was higher in triple-negative basal like tumors than in non-basal like tumors, including luminal A, luminal B and HER2-enriched subtypes. Collectively, this comprehensive Fra-1 interaction profiling provides a broad and deep view of Fra-1 chromatin interaction landscape, which will help in deciphering mechanisms of AP-1 regulation of gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112962 | GEO | 2019/09/03

REPOSITORIES: GEO

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Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Project description:Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor growth. Here we report the identification of 118 proteins interacting with endogenous chromatin-bound Fra-1 in TNBC cells, highlighting DDX5 as the most enriched Fra-1-interacting protein. DDX5, a previously unrecognized protein in the Fra-1 transcriptional network, shows extensive overlap with Fra-1 cistrome and transcriptome that are highly associated with the TNBC cell growth. We provide evidence that DDX5 expression enhances Fra-1 transcriptional activity and potentiates Fra-1-driven cell proliferation. Furthermore, we show that the DDX5 target gene signature predicts poor clinical outcome in breast cancer patients. DDX5 protein level was higher in triple-negative basal-like tumors than in non-basal-like tumors, including luminal A, luminal B, and HER2-enriched subtypes. Collectively, by combining proteomic and genomic approaches we reveal a role for DDX5 as a regulatory protein of Fra-1 signaling and suggest DDX5 as a potential therapeutic target for TNBC.

2019-09-03 | GSE112963 | GEO

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1 [ChIP-seq]

Project description:Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor progression. However, a systematic analysis of the composition of the Fra-1 protein network specifically on chromatin is still missing. Here we performed endogenous purification of Fra-1 transcriptional complex under ChIP conditions, followed by mass spectrometry, to identify chromatin-bound partners of Fra-1 in TNBC cells. This study allowed the identification of 118 interactors, highlighting DDX5 as the high ranking of Fra-1 interacting proteins. DDX5, a previously unrecognized protein in the network, is recruited globally to Fra-1 binding sites and shares a substantial set of Fra-1 target genes required for the TNBC cell growth. We provide evidence that DDX5 expression enhances Fra-1 transcriptional activity, thereby enhancing Fra-1-driven tumorigenesis. By integrating ChIP-seq and RNA-seq, we show that DDX5 target gene signature predicts poor clinical outcome in breast cancer patients. DDX5 protein level was higher in triple-negative basal like tumors than in non-basal like tumors, including luminal A, luminal B and HER2-enriched subtypes. Collectively, this comprehensive Fra-1 interaction profiling provides a broad and deep view of Fra-1 chromatin interaction landscape, which will help in deciphering mechanisms of AP-1 regulation of gene expression.

2019-09-03 | GSE112961 | GEO

Blocking Fra-1 sensitizes triple-negative breast cancer to olaparib

Project description:Fra-1 (FOSL1) is overexpressed in triple-negative breast cancer (TNBC). Fra-1 is a member of the activator protein 1 (AP-1) transcription factor complex, which plays crucial roles in tumor progression and treatment resistance. We have previously identified 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells in a large screen, and these included PARP1(Poly (ADP-ribose) polymerase 1). PARP1 inhibitor olaparib is currently in clinical use for treatment of BRCA-mutated TNBC breast cancer. Here, we demonstrate that this interaction impacts the efficacy of olaparib treatment. We corroborate that PARP1 interacts with Fra-1, and we show that PARP1 downregulates Fra-1 and consequently reduces AP-1 transcriptional activity. Inhibition of PARP1, on the other hand, increases Fra-1 levels and enhances its transcriptional activity, which in turn can increase treatment resistance. However, by inhibiting Fra-1, we found that TNBC cells became sensitized to olaparib treatment. We compared Fra-1 chromatin binding sites with the Fra-1 and PARP1 regulated transcriptomes, and found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We further show that PARP1 protein levels significantly correlate with Fra-1 in clinical breast cancer tumors, and we identify that high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall, but not in basal-like tumors. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a therapeutic approach to improve olaparib treatment outcome for TNBC patients.

2022-04-21 | GSE149621 | 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

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

Identification of Fra-1/AP-1 binding sites in macrophages

Project description:The polarization and activation of macrophages are controlled synergistically by transcription factors such as NF-κB and AP-1 transcription factor members. Surprisingly, little is known about the role of the AP-1 member, Fra-1, during macrophage responses. To determine the full spectrum of Fra-1 binding sites in macrophages, chromatin immunoprecipitation sequencing analysis was performed in macrophages pooling down for the transcription factor Fra-1.

2021-06-25 | GSE178865 | GEO

Transcript profiling in peritoneal macrophages from wildtype, Fra-1ΔMxCre or Fra-2ΔLysMCre mice

Project description:The polarization and activation of macrophages are controlled synergistically by transcription factors such as NF-κB and AP-1 transcription factor members. Surprisingly, little is known about the role of the Fra proteins, both members of the AP-1 transcription factor family, in macrophage activity. To determine the full profile of Fra network, microarray RNA expression analysis using Agilent Technologies platform was performed in wild-type, Fra-1ΔMxCre or Fra-2ΔLysMCre macrophages.

2021-05-17 | GSE128787 | GEO

Identification of Fra-1 and/or Fra-2 regulated genes in MDA-MB231 cells

Project description:In the paper "Fra-1 regulates its target genes via binding to remote enhancers without exerting major control on chromatin architecture in triple negative breast cancers" by Bejjani et al., we identified Fra-1 and/or Fra-2 target genes in MDA-MB-231 cells. si RNA against Fra-1 and against Fra-2 were transfected in MDA-MB-231 cells either independenlty or simultaneously to identify genes regulated specifically by Fra-1 or Fra-2 and genes regulated redundantly or complementarily by Fra-1 and Fra-2 total RNA were purified and biotinylated sense-strand cDNA were produced. cDNA targets were used to probe Affymetrix GeneChip Human Gene 2.0 ST arrays

2021-02-23 | GSE146823 | GEO

Expression data of A549 Fra-2 overexpressing cells

Project description:Fra-2 belongs to the activated protein-1 (AP-1) family and is involved in the mechanisms of resistance to platinum in ovarian cancer and to anti-EGFR therapy in NSCLC. We used microarrays to identify genes potentially regulated by Fra-2 transciptional activity.

2022-09-23 | GSE213816 | GEO

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