Expression of the protein phosphatase 1 inhibitor KEPI is downregulated in breast cancer cell lines and tissues and involved in the regulation of the tumor suppressor EGR1 via the MEK-ERK pathway

Wenzel, Katrin; Daskalow, Katjana; Herse, Florian; Seitz, Susanne; Zacharias, Ute; Schenk, Jörg A.; Schulz, Herbert; Hübner, Norbert; Micheel, Burkhard; Schlag, Peter M.; Osterziel, Karl Josef; Özcelik, Cemil; Scherneck, Siegfried; Jandrig, Burkhard

doi:10.1515/bc.2007.062

Cited by 17 publications

(11 citation statements)

References 27 publications

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“…We have previously reported decreases in EGR1 levels in synovial sarcoma (15) and others have implicated decrease in EGR1 in a wide range of tumors (26)(27)(28)(29). To verify whether EGR1 is a bona fide target of miR-183, we transfected a reporter containing the 3'UTR of EGR1 in a variety of tumor cell lines, such as FUJI and SYO-1 (synovial sarcoma) and RH30 and JR1 (RMS), all of which expressed high levels of miR-183.…”

Section: Mir-183 Regulates Egr1 Levels Through Binding Its 3'utrmentioning

confidence: 84%

MicroRNA miR-183 Functions as an Oncogene by Targeting the Transcription FactorEGR1and Promoting Tumor Cell Migration

2010

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The transcription factor EGR1 is a tumor suppressor gene that is downregulated in many cancer types. Clinically, loss of EGR1 translates to increased tumor transformation and subsequent patient morbidity and mortality. In synovial sarcoma, the SS18-SSX fusion protein represses EGR1 expression through a direct association with the EGR1 promoter. However, the mechanism through which EGR1 becomes downregulated in other tumor types is unclear. Here, we report that EGR1 is regulated by microRNA (miR)-183 in multiple tumor types including synovial sarcoma, rhabdomyosarcoma (RMS), and colon cancer. Using an integrative network analysis, we identified that miR-183 is significantly overexpressed in these tumor types as well as in corresponding tumor cell lines. Bioinformatic analyses suggested that miR-183 could target EGR1 mRNA and this specific interaction was validated in vitro. miR-183 knockdown in synovial sarcoma, RMS, and colon cancer cell lines revealed deregulation of a miRNA network composed of miR-183-EGR1-PTEN in these tumors. Integrated miRNA-and mRNA-based genomic analyses indicated that miR-183 is an important contributor to cell migration in these tumor types and this result was functionally validated to be occurring via an EGR1-based mechanism. In conclusion, our findings have significant implications in the mechanisms underlying EGR1 regulation in cancers. miR-183 has a potential oncogenic role through the regulation of 2 tumor suppressor genes, EGR1 and PTEN, and the deregulation of this fundamental miRNA regulatory network may be central to many tumor types. Cancer Res; 70(23); 9570-80. Ó2010 AACR.

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Section: Mir-183 Regulates Egr1 Levels Through Binding Its 3'utrmentioning

confidence: 84%

MicroRNA miR-183 Functions as an Oncogene by Targeting the Transcription FactorEGR1and Promoting Tumor Cell Migration

2010

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“…DUSP2 and DUSP5 induction meet the criteria of being dependent on mitogenic signaling and on MK, as MK3OE and MKi, enhance and decrease DUSP mRNA induction, respectively (Figure 3G). To validate the involvement of DUSPs in the negative regulatory network involving MK3, we used induction of EGR1 as a read-out for mitogen-induced ERK activity [37]. MKi cells display a stronger EGR1 induction (Additional file 4: Figure S4A), consistent with loss of negative regulation via ERK.…”

Section: Resultsmentioning

confidence: 99%

MK3 controls Polycomb target gene expression via negative feedback on ERK

Prickaerts

Niessen

Mouchel-Vielh

et al. 2012

Epigenetics & Chromatin

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BackgroundGene-environment interactions are mediated by epigenetic mechanisms. Polycomb Group proteins constitute part of an epigenetic cellular transcriptional memory system that is subject to dynamic modulation during differentiation. Molecular insight in processes that control dynamic chromatin association and dissociation of Polycomb repressive complexes during and beyond development is limited. We recently showed that MK3 interacts with Polycomb repressive complex 1 (PRC1). The functional relevance of this interaction, however, remained poorly understood. MK3 is activated downstream of mitogen- and stress-activated protein kinases (M/SAPKs), all of which fulfill crucial roles during development. We here use activation of the immediate-early response gene ATF3, a bona fide PRC1 target gene, as a model to study how MK3 and its effector kinases MAPK/ERK and SAPK/P38 are involved in regulation of PRC1-dependent ATF3 transcription.ResultsOur current data show that mitogenic signaling through ERK, P38 and MK3 regulates ATF3 expression by PRC1/chromatin dissociation and epigenetic modulation. Mitogenic stimulation results in transient P38-dependent H3S28 phosphorylation and ERK-driven PRC1/chromatin dissociation at PRC1 targets. H3S28 phosphorylation by itself appears not sufficient to induce PRC1/chromatin dissociation, nor ATF3 transcription, as inhibition of MEK/ERK signaling blocks BMI1/chromatin dissociation and ATF3 expression, despite induced H3S28 phosphorylation. In addition, we establish that concomitant loss of local H3K27me3 promoter marking is not required for ATF3 activation. We identify pERK as a novel signaling-induced binding partner of PRC1, and provide evidence that MK3 controls ATF3 expression in cultured cells via negative regulatory feedback on M/SAPKs. Dramatically increased ectopic wing vein formation in the absence of Drosophila MK in a Drosophila ERK gain-of-function wing vein patterning model, supports the existence of MK-mediated negative feedback regulation on pERK.ConclusionWe here identify and characterize important actors in a PRC1-dependent epigenetic signal/response mechanism, some of which appear to be nonspecific global responses, whereas others provide modular specificity. Our findings provide novel insight into a Polycomb-mediated epigenetic mechanism that dynamically controls gene transcription and support a direct link between PRC1 and cellular responses to changes in the microenvironment.

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“…With the exception of (ZFP161, TFDP1, PITX2), the functions of (Sp1, NRF1, E2F1, TFAP2A, EGR-1) and their functional relevance to estrogen action in breast cancer cells have been extensively documented in [29-32]. …”

Section: Discussionmentioning

confidence: 99%

A modulated empirical Bayes model for identifying topological and temporal estrogen receptor α regulatory networks in breast cancer

et al. 2011

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BackgroundEstrogens regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. Dynamic gene expression changes have been shown to characterize the breast cancer cell response to estrogens, the every molecular mechanism of which is still not well understood.ResultsWe developed a modulated empirical Bayes model, and constructed a novel topological and temporal transcription factor (TF) regulatory network in MCF7 breast cancer cell line upon stimulation by 17β-estradiol stimulation. In the network, significant TF genomic hubs were identified including ER-alpha and AP-1; significant non-genomic hubs include ZFP161, TFDP1, NRF1, TFAP2A, EGR1, E2F1, and PITX2. Although the early and late networks were distinct (<5% overlap of ERα target genes between the 4 and 24 h time points), all nine hubs were significantly represented in both networks. In MCF7 cells with acquired resistance to tamoxifen, the ERα regulatory network was unresponsive to 17β-estradiol stimulation. The significant loss of hormone responsiveness was associated with marked epigenomic changes, including hyper- or hypo-methylation of promoter CpG islands and repressive histone methylations.ConclusionsWe identified a number of estrogen regulated target genes and established estrogen-regulated network that distinguishes the genomic and non-genomic actions of estrogen receptor. Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed.

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Expression of the protein phosphatase 1 inhibitor KEPI is downregulated in breast cancer cell lines and tissues and involved in the regulation of the tumor suppressor EGR1 via the MEK-ERK pathway

Cited by 17 publications

References 27 publications

MicroRNA miR-183 Functions as an Oncogene by Targeting the Transcription FactorEGR1and Promoting Tumor Cell Migration

MicroRNA miR-183 Functions as an Oncogene by Targeting the Transcription FactorEGR1and Promoting Tumor Cell Migration

MK3 controls Polycomb target gene expression via negative feedback on ERK

A modulated empirical Bayes model for identifying topological and temporal estrogen receptor α regulatory networks in breast cancer

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