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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.

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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.

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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.

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

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