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Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERalpha-positive breast tumorigenesis

ABSTRACT: The human RNA polymerase II-associated factor complex (hPAFc) and its individual subunits have been implicated in human diseases including cancer. However, its involvement in breast cancer cells awaits investigation. Using data mining and human breast cancer tissue microarrays, we found that Ctr9, the key scaffold subunit in hPAFc, is highly expressed in ERα+ luminal breast cancer and the high expression of Ctr9 correlates with poor prognosis. Knockdown of Ctr9 in ERα+ breast cancer cells almost completely erased estrogen regulated transcriptional response. At the molecular level, Ctr9 enhances ERα protein stability, promotes recruitment of ERα and RNAPII and stimulates transcription elongation and transcription-coupled histone modifications. Knockdown of Ctr9, but not other hPAFc subunits, alters the morphology, proliferative capacity and tamoxifen-sensitivity of ERα+ breast cancer cells. Together, our study reveals that Ctr9, a key subunit of hPAFc, is a central regulator of estrogen signaling that drives ERα+ breast tumorigenesis, rendering it a potential target for the treatment of ERα+ breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73388 | GEO | 2015/09/25

SECONDARY ACCESSION(S): PRJNA296868

REPOSITORIES: GEO

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Systematic identification of Ctr9 regulome in ERα-positive breast cancer

Project description:Ctr9, the key scaffold subunit of the human RNA polymerase II (RNAPII) associated factor complex (PAFc), has been demonstrated as a positive regulator of ERα-positive breast cancer progression and ERα-target gene expression. Previously, we found that knockdown of Ctr9 reduces ERα protein stability and decreases the occupancy of ERα and RNAPII at select ERα-target genes. However, the genome-wide regulation of the occupancy of ERα and RNAPII mediated by Ctr9 is still unclear. Here, we determined the genome-wide ERα and RNAPII occupancy in response to estrogen induction and/or Ctr9 knockdown by performing chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq). We found that loss of Ctr9 dramatically decreases the global occupancy of ERα and RNAPII, highlighting the significance of Ctr9 in regulating estrogen signaling in ERα-positive breast cancer cells. Combining this resource with previously published genomic data sets, we identified a unique subset of ERα and Ctr9 target genes, and further delineates the possible independent function of Ctr9 from other subunits in PAFc.

2016-10-10 | GSE80728 | GEO

Determine the chromatin association change of H3K27me3 and PRC2 in response to CTR9 inducible loss as well as genome-wide mapping of Flag-CTR9 binding sites in MCF7 cells

Project description:CTR9 is the scaffold subunit in PAFc (Polymerase associated factor complex), a multifunctional complex employed in multiple steps of RNA Pol II-mediated transcription. CTR9/PAFc is well known as an evolutionarily conserved elongation factor regulating gene activation via coupling with histone modifications enzymes. However, little is known about its function to restrain repressive histone markers. Using inducible and stable CTR9 knockdown breast cancer cell lines, we discovered that the amount of H3K27me3 is strictly controlled by CTR9. Quantitative profiling on histone modifications revealed a striking increase of H3K27me3 level upon loss of CTR9. Moreover, loss of CTR9 leads to genome-wide expansion of H3K27me3, as well as increased recruitment of PRC2 on chromatin, which can be reversed by CTR9 restoration. Moreover, CTR9 depletion triggers a PRC2 subtype switch from less active PRC2.2 to PRC2.1 with higher methyltransferase activity. As a consequence, CTR9 depletion generates vulnerability that renders breast cancer cells hypersensitive to PRC2 inhibitors. Our findings that CTR9 demarcates PRC2-mediated H3K27me3 levels and genomic distribution provide a unique mechanism of transition from transcriptionally active to repressive chromatin states and shed light on the biological functions of CTR9 in development and cancer.

2021-10-19 | GSE173176 | GEO

Cohesin is required for expression of the estrogen receptor-alpha (ESR1) gene

Project description:In this study we show that depletion of the cohesin subunit SMC3 or the Mediator subunit MED12 significantly impairs the ERα-regulated transcriptome. Surprisingly, SMC3 depletion appears to elicit this effect indirectly by rapidly decreasing ESR1 transcription and ERα protein levels. Moreover, we provide evidence that both SMC3 and MED12 colocalize on the ESR1 gene and are mutually required for occupancy as well as for transcriptional elongation. Finally, we show that extended proteasome inhibition decreases the mRNA expression of cohesin subunits which accompanies a decrease in ESR1 mRNA and ERα protein levels as well as estrogen-regulated transcription. Conclusions: These results identify the ESR1 gene as a cohesin/Mediator-dependent gene and indicate that this regulation may potentially be exploited for the treatment of estrogen-dependent breast cancer. This set contains 18 microarray samples with triplicates for each condition. 3 control siRNA, 3 control estrogen stimulated, 3 siRNA Med12 knockdown, 3 siRNA Med12 knockdown estrogen stimulated, 3 siRNA Smc3 knockdown, 3 siRNA Smc3 knockdown estrogen stimulated.

2013-05-20 | E-GEOD-38252 | biostudies-arrayexpress

Candidate ERalpha targets for DNA methylation-mediated gene silencing

Project description:DNA methylation of specific CpG sites associates with estrogen receptor α (ERα)-positive status in human breast cancer. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was tested in a panel of antihormone-resistant T47D and MCF-7 cells with varying levels of ERα expression/activity that were derived by long-term fulvestrant treatment and by estrogen deprivation. Using Agilent’s Whole Human Genome 4x44K v2 gene expression microarrays, the intersection of ERα inversely-related genes and genes induced by the DNA methyltransferase-inhibitor decitabine were identified and revealed 39 candidate ERα DNA methylation targets. Enrichment analysis indicated over-representation of ERα-binding sites, basal-up/luminal-down markers, cancer stem cell genes, epithelial-mesenchymal transition (EMT) genes, inflammatory genes and tumor suppressors. Kaplan-Meier survival curve and Cox proportional hazard regression analyses indicated these candidate targets predicted poor distant metastasis-free survival among 2,116 breast cancer patients. The basal and EMT genes LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites, therefore they were selected for validation. LCN2 and IFI27 CpG methylation levels, quantitated by pyrosequencing, were inversely related to ERα expression/activity in wild-type and antihormone-resistant ERα-negative T47D cells, in ERα-negative T47D cells infected with lentiviral ERα, and in a panel of 11 breast cancer cell lines. Implications: ERα directs DNA methylation-mediated silencing of specific genes, such as basal markers, and thereby may in part program breast cancers as the prognostically more favorable luminal subtype. Thus, genes that can be methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.

2017-02-05 | GSE85536 | GEO

Determine the chromatin association change of H3K27me3 and PRC2 in response to PRC2 subtype change or stable CTR9 KD in MCF7 cells

2021-12-02 | GSE189796 | GEO

Nuclear Estrogen Receptor alpha (ERα) interactome following estrogen and antiestrogen treatment.

Project description:The Estrogen Receptor alpha (ERα) controls key cellular functions in hormone responsive breast cancer by assembling in large functional multiprotein complexes. ERα ligands are classified as agonists and antagonist, according to the response they elicit, thus the molecular characterization of the of ERα nuclear iteractome composition following estrogen and antiestrogen stimulation whose is needed to understand their effects on estrogen target tissues, in particular breast cancer. To this aim interaction proteomics coupled to mass spectrometry (MS) was applied to map the ERα nuclear interacting partners in MCF7 breast cancer cell nuclei following estrogen and antiestrogen stimuli.

2020-09-02 | PXD018709 | Pride

Cohesin is required for expression of the estrogen receptor-alpha (ESR1) gene

2013-05-20 | GSE38252 | GEO

Multiple Histone modifications ChIP-seq in MCF7 cells corresponding to Ctr9 KD (paper title: Ctr9, the scaffold subunit of PAFc, govens PRC2-mediated H3K27me3 domains in breast cancer cells)

Project description:We want to examine the alternation of histone modification spectrum on chormatin in corresponding to Ctr9 loss either in an inducible KD or stable KD fashion in MCF7 breast cancer cells.

2022-06-25 | GSE133318 | GEO

Proteasome inhibition blocks estrogen-dependent gene transcription by decreasing histone H2B monoubiquitination in human breast cancer cells

Project description:The estrogen receptor-alpha (ERα) determines breast cancer cell phenotype and is a prognostic indicator. A better understanding of the mechanisms controlling ERα function may uncover improved strategies for the treatment of breast cancer. Proteasome inhibition was previously reported to regulate estrogen-induced transcription but the mechanisms by which it influences ERα function remain controversial. In this study we investigated the transcriptome-wide effects of the proteasome inhibitor Velcade on estrogen-regulated transcription in MCF7 human breast cancer cells and demonstrate a specific global decrease in estrogen-induced transcription. This set contains 12 microarray samples. 3 controls, 3 estrogen stimulated, 3 Bortezomib stimulated, 3 Bortezomib + estrogen stimulated

2011-11-22 | E-GEOD-30931 | biostudies-arrayexpress

CTR9 affects virulence of Candida albicans by regulating methionine metabolism

Project description:Project Abstract : Paf1C is a general transcription regulator and is associated with various human diseases. One of its subunits, CTR9, is known as a structurally and functionally core component of Paf1C. While its role in higher eukaryotes have been researched, the association between the core component and human fungal pathogen is not fully understood yet. During pre-infection process, Candida albicans adheres to the surface of hosts and sufficiently grows as the circular form. Under immune deficiency condition, C. albicans enters into the infection process and forms hyphae. Here, we performed virulence tests and transcriptome analysis to identify the role of CTR9 in two infection stages. In pre-infection process, CTR9 regulates basic cellular processes and metabolism, affecting cell growth. Of metabolic processes, methionine biosynthetic genes are significantly dependent on CTR9. This pathway hardly affects cell abundance for pre-infection stage, but has considerable effect on hyphal formation during infection stage. Therefore, it shows that methionine biosynthetic pathway mediated by CTR9 is essential for pathogenesis of C. albicans.

2023-11-30 | GSE244665 | GEO

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