Wegwitz, Florian

[["dc.bibliographiccitation.firstpage","37906"],["dc.bibliographiccitation.issue","35"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","37918"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Kosinsky, Robyn L."],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Hellbach, Nicole"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Mansouri, Ahmed"],["dc.contributor.author","Vogel, Tanja"],["dc.contributor.author","Begus-Nahrmann, Yvonne"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2019-07-09T11:42:03Z"],["dc.date.available","2019-07-09T11:42:03Z"],["dc.date.issued","2015-11-10"],["dc.description.abstract","Epigenetic regulatory mechanisms play a central role in controlling gene expression during development, cell differentiation and tumorigenesis. Monoubiquitination of histone H2B is one epigenetic modification which is dynamically regulated by the opposing activities of specific ubiquitin ligases and deubiquitinating enzymes (DUBs). The Ubiquitin-specific Protease 22 (USP22) is the ubiquitin hydrolase component of the human SAGA complex which deubiquitinates histone H2B during transcription. Recently, many studies have investigated an oncogenic potential of USP22 overexpression. However, its physiological function in organ maintenance, development and its cellular function remain largely unknown. A previous study reported embryonic lethality in Usp22 knockout mice. Here we describe a mouse model with a global reduction of USP22 levels which expresses the LacZ gene under the control of the endogenous Usp22 promoter. Using this reporter we found Usp22 to be ubiquitously expressed in murine embryos. Notably, adult Usp22lacZ/lacZ displayed low residual Usp22 expression levels coupled with a reduced body size and weight. Interestingly, the reduction of Usp22 significantly influenced the frequency of differentiated cells in the small intestine and the brain while H2B and H2Bub1 levels remained constant. Taken together, we provide evidence for a physiological role for USP22 in controlling cell differentiation and lineage specification."],["dc.identifier.doi","10.18632/oncotarget.5412"],["dc.identifier.pmid","26431380"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12736"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58576"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1949-2553"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Usp22 deficiency impairs intestinal epithelial lineage specification in vivo."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","7"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Clinical Epigenetics"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Pantelaiou-Prokaki, Garyfallia"],["dc.contributor.author","Mieczkowska, Iga"],["dc.contributor.author","Schmidt, Geske E."],["dc.contributor.author","Fritzsche, Sonja"],["dc.contributor.author","Prokakis, Evangelos"],["dc.contributor.author","Gallwas, Julia"],["dc.contributor.author","Wegwitz, Florian"],["dc.date.accessioned","2022-02-01T10:31:32Z"],["dc.date.accessioned","2022-08-18T12:33:13Z"],["dc.date.available","2022-02-01T10:31:32Z"],["dc.date.available","2022-08-18T12:33:13Z"],["dc.date.issued","2022-01-11"],["dc.date.updated","2022-07-29T12:00:15Z"],["dc.description.abstract","Background Basal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer. Resistance to chemotherapy is the main cause of treatment failure in BLBC. Therefore, novel therapeutic strategies counteracting the gain of aggressiveness underlying therapy resistance are urgently needed. The epithelial-to-mesenchymal transition (EMT) has been established as one central process stimulating cancer cell migratory capacity but also acquisition of chemotherapy-resistant properties. In this study, we aimed to uncover epigenetic factors involved in the EMT-transcriptional program occurring in BLBC cells surviving conventional chemotherapy. Results Using whole transcriptome data from a murine mammary carcinoma cell line (pG-2), we identified upregulation of Hdac4 , 7 and 8 in tumor cells surviving conventional chemotherapy. Subsequent analyses of human BLBC patient datasets and cell lines established HDAC8 as the most promising factor sustaining tumor cell viability. ChIP-sequencing data analysis identified a pronounced loss of H3K27ac at regulatory regions of master transcription factors (TFs) of epithelial phenotype like Gata3 , Elf5 , Rora and Grhl2 upon chemotherapy. Interestingly, impairment of HDAC8 activity reverted epithelial-TFs levels. Furthermore, loss of HDAC8 activity sensitized tumor cells to chemotherapeutic treatments, even at low doses. Conclusion The current study reveals a previously unknown transcriptional repressive function of HDAC8 exerted on a panel of transcription factors involved in the maintenance of epithelial cell phenotype, thereby supporting BLBC cell survival to conventional chemotherapy. Our data establish HDAC8 as an attractive therapeutically targetable epigenetic factor to increase the efficiency of chemotherapeutics. Graphical abstract"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.citation","Clinical Epigenetics. 2022 Jan 11;14(1):7"],["dc.identifier.doi","10.1186/s13148-022-01228-4"],["dc.identifier.pii","1228"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/98885"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112916"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-517"],["dc.publisher","BioMed Central"],["dc.relation.eissn","1868-7083"],["dc.relation.issn","1868-7075"],["dc.rights","CC BY 4.0"],["dc.rights.holder","The Author(s)"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","HDAC8"],["dc.subject","MET"],["dc.subject","EMT"],["dc.subject","BLBC"],["dc.subject","TNBC"],["dc.subject","Chemotherapy"],["dc.subject","Epigenetics"],["dc.subject","H3K27ac"],["dc.subject","Epithelial transcription factors"],["dc.title","HDAC8 suppresses the epithelial phenotype and promotes EMT in chemotherapy-treated basal-like breast cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","6334"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Nucleic Acids Research"],["dc.bibliographiccitation.lastpage","6349"],["dc.bibliographiccitation.volume","45"],["dc.contributor.author","Mishra, Vivek Kumar"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Kosinsky, Robyn Laura"],["dc.contributor.author","Sen, Madhobi"],["dc.contributor.author","Baumgartner, Roland"],["dc.contributor.author","Wulff, Tanja"],["dc.contributor.author","Siveke, Jens T."],["dc.contributor.author","Schildhaus, Hans-Ulrich"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Kohlhof, Hella"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2018-11-07T10:22:37Z"],["dc.date.available","2018-11-07T10:22:37Z"],["dc.date.issued","2017"],["dc.description.abstract","Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class Ispecific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGF beta signaling and inhibits TGF beta-induced epithelial-tomesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 (CDKN1A) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202-induced genes were enriched for Bromodomain-containing Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACi-mediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2017"],["dc.identifier.doi","10.1093/nar/gkx212"],["dc.identifier.isi","000403693000023"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14605"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42309"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","1362-4962"],["dc.relation.issn","0305-1048"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4-and MYC-dependent manner"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2616"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Cells"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Kolb, Katharina"],["dc.contributor.author","Hellinger, Johanna"],["dc.contributor.author","Kansy, Maike"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Bauerschmitz, Gerd"],["dc.contributor.author","Emons, Günter"],["dc.contributor.author","Gründker, Carsten"],["dc.date.accessioned","2021-04-14T08:26:32Z"],["dc.date.available","2021-04-14T08:26:32Z"],["dc.date.issued","2020"],["dc.description.sponsorship","Deutsche Krebshilfe"],["dc.identifier.doi","10.3390/cells9122616"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81981"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.publisher","MDPI"],["dc.relation.eissn","2073-4409"],["dc.rights","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Influence of ARHGAP29 on the Invasion of Mesenchymal-Transformed Breast Cancer Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Cell Death & Disease"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Kosinsky, Robyn Laura"],["dc.contributor.author","Helms, Marlena"],["dc.contributor.author","Zerche, Maria"],["dc.contributor.author","Wohn, Luisa"],["dc.contributor.author","Dyas, Anna"],["dc.contributor.author","Prokakis, Evangelos"],["dc.contributor.author","Kazerouni, Zahra Basir"],["dc.contributor.author","Bedi, Upasana"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2020-12-10T18:09:43Z"],["dc.date.available","2020-12-10T18:09:43Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1038/s41419-019-2141-9"],["dc.identifier.eissn","2041-4889"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17081"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/73737"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Clinical Epigenetics"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Sen, Madhobi"],["dc.contributor.author","Wang, Xin"],["dc.contributor.author","Hamdan, Feda H."],["dc.contributor.author","Rapp, Jacobe"],["dc.contributor.author","Eggert, Jessica"],["dc.contributor.author","Kosinsky, Robyn Laura"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Kutschat, Ana Patricia"],["dc.contributor.author","Younesi, Fereshteh S."],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Papantonis, Argyris"],["dc.contributor.author","Strӧbel, Philipp"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2020-12-10T18:39:06Z"],["dc.date.available","2020-12-10T18:39:06Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1186/s13148-019-0690-5"],["dc.identifier.eissn","1868-7083"],["dc.identifier.issn","1868-7075"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16438"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77543"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","ARID1A facilitates KRAS signaling-regulated enhancer activity in an AP1-dependent manner in colorectal cancer cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","178"],["dc.bibliographiccitation.journal","BMC Cancer"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","Maenz, Claudia"],["dc.contributor.author","Lenfert, Eva"],["dc.contributor.author","Pantel, Klaus"],["dc.contributor.author","Schumacher, Udo"],["dc.contributor.author","Deppert, Wolfgang R."],["dc.contributor.author","Wegwitz, Florian"],["dc.date.accessioned","2018-11-07T09:59:27Z"],["dc.date.available","2018-11-07T09:59:27Z"],["dc.date.issued","2015"],["dc.description.abstract","Background: Experimental analysis of the metastatic cascade requires suitable model systems which allow tracing of disseminated tumor cells and the identification of factors leading to metastatic outgrowth in distant organs. Such models, especially models using immune-competent mice, are rather scarce. We here analyze tumor cell dissemination and metastasis in an immune-competent transplantable mouse mammary tumor model, based on the SV40 transgenic WAP-T mouse mammary carcinoma model. Methods: We orthotopically transplanted into immune-competent WAP-T mice two tumor cell lines (H8N8, moderately metastatic, and G-2, non-metastatic), developed from primary WAP-T tumors. G-2 and H8N8 cells exhibit stem cell characteristics, form homeostatic, heterotypic tumor cell systems in vitro, and closely mimic endogenous primary tumors after orthotopic transplantation into syngeneic, immune-competent WAP-T mice. Tumor cell transgene-specific PCR allows monitoring of tumor cell dissemination into distinct organs, and immunohistochemistry for SV40 T-antigen tracing of single disseminated tumor cells (DTC). Results: While only H8N8 cell-derived tumors developed metastases, tumors induced with both cell lines disseminated into a variety of organs with similar efficiency and similar organ distribution. H8N8 metastases arose only in lungs, indicating that organ-specific metastatic outgrowth depends on the ability of DTC to re-establish a tumor cell system rather than on invasion per se. Resection of small tumors (0.5 cm(3)) prevented metastasis of H8N8-derived tumors, most likely due to the rather short half-life of DTC, and thus to shorter exposure of the mice to DTC. In experimental metastasis by tail vein injection, G-2 and H8N8 cells both were able to form lung metastases with similar efficiency. However, after injection of sorted \"mesenchymal\" and \"epithelial\" G-2 cell subpopulations, only the \"epithelial\" subpopulation formed lung metastases. Conclusions: We demonstrate the utility of our mouse model to analyze factors influencing tumor cell dissemination and metastasis. We suggest that the different metastatic capacity of G-2 and H8N8 cells is due to their different degrees of epithelial-mesenchymal plasticity (EMP), and thus the ability of the respective disseminated cells to revert from a \"mesenchymal\" to an \"epithelial\" differentiation state."],["dc.identifier.doi","10.1186/s12885-015-1165-5"],["dc.identifier.isi","000352060400001"],["dc.identifier.pmid","25886487"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12004"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/37589"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1471-2407"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Epithelial-mesenchymal plasticity is a decisive feature for the metastatic outgrowth of disseminated WAP-T mouse mammary carcinoma cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","32"],["dc.bibliographiccitation.journal","Genome Biology"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Xie, Wanhua"],["dc.contributor.author","Nagarajan, Sankari"],["dc.contributor.author","Baumgart, Simon J."],["dc.contributor.author","Kosinsky, Robyn Laura"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Hennion, Magali"],["dc.contributor.author","Indenbirken, Daniela"],["dc.contributor.author","Bonn, Stefan"],["dc.contributor.author","Grundhoff, Adam"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Mansouri, Ahmed"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2018-11-07T10:27:18Z"],["dc.date.available","2018-11-07T10:27:18Z"],["dc.date.issued","2017"],["dc.description.abstract","Background: Monoubiquitination of H2B (H2Bub1) is a largely enigmatic histone modification that has been linked to transcriptional elongation. Because of this association, it has been commonly assumed that H2Bub1 is an exclusively positively acting histone modification and that increased H2Bub1 occupancy correlates with increased gene expression. In contrast, depletion of the H2B ubiquitin ligases RNF20 or RNF40 alters the expression of only a subset of genes. Results: Using conditional Rnf40 knockout mouse embryo fibroblasts, we show that genes occupied by low to moderate amounts of H2Bub1 are selectively regulated in response to Rnf40 deletion, whereas genes marked by high levels of H2Bub1 are mostly unaffected by Rnf40 loss. Furthermore, we find that decreased expression of RNF40-dependent genes is highly associated with widespread narrowing of H3K4me3 peaks. H2Bub1 promotes the broadening of H3K4me3 to increase transcriptional elongation, which together lead to increased tissue- specific gene transcription. Notably, genes upregulated following Rnf40 deletion, including Foxl2, are enriched for H3K27me3, which is decreased following Rnf40 deletion due to decreased expression of the Ezh2 gene. As a consequence, increased expression of some RNF40-\"suppressed\" genes is associated with enhancer activation via FOXL2. Conclusion: Together these findings reveal the complexity and context-dependency whereby one histone modification can have divergent effects on gene transcription. Furthermore, we show that these effects are dependent upon the activity of other epigenetic regulatory proteins and histone modifications."],["dc.identifier.doi","10.1186/s13059-017-1159-5"],["dc.identifier.isi","000394828000003"],["dc.identifier.pmid","28209164"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14250"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43221"],["dc.notes.intern","Merged from goescholar"],["dc.notes.intern","In goescholar not merged with http://resolver.sub.uni-goettingen.de/purl?gs-1/14993 but duplicate"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1474-760X"],["dc.rights","CC BY 4.0"],["dc.rights.access","openAccess"],["dc.rights.holder","The Author(s)."],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","RNF40 regulates gene expression in an epigenetic context-dependent manner"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e154475"],["dc.bibliographiccitation.issue","16"],["dc.bibliographiccitation.journal","JCI Insight"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Krebs, Niklas"],["dc.contributor.author","Klein, Lukas"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Espinet, Elisa"],["dc.contributor.author","Maurer, Hans Carlo"],["dc.contributor.author","Tu, Mengyu"],["dc.contributor.author","Penz, Frederike"],["dc.contributor.author","Küffer, Stefan"],["dc.contributor.author","Xu, Xingbo"],["dc.contributor.author","Bohnenberger, Hanibal"],["dc.contributor.author","Singh, Shiv K."],["dc.date.accessioned","2022-09-01T09:50:53Z"],["dc.date.available","2022-09-01T09:50:53Z"],["dc.date.issued","2022"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1172/jci.insight.154475"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113823"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-597"],["dc.relation.eissn","2379-3708"],["dc.title","Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","1118"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Cell Death & Disease"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Mieczkowska, Iga K."],["dc.contributor.author","Pantelaiou-Prokaki, Garyfallia"],["dc.contributor.author","Prokakis, Evangelos"],["dc.contributor.author","Schmidt, Geske E."],["dc.contributor.author","Müller-Kirschbaum, Lukas C."],["dc.contributor.author","Werner, Marcel"],["dc.contributor.author","Sen, Madhobi"],["dc.contributor.author","Velychko, Taras"],["dc.contributor.author","Jannasch, Katharina"],["dc.contributor.author","Dullin, Christian"],["dc.contributor.author","Wegwitz, Florian"],["dc.date.accessioned","2022-01-11T14:05:43Z"],["dc.date.available","2022-01-11T14:05:43Z"],["dc.date.issued","2021"],["dc.description.abstract","Breast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping with the triple-negative BC subtype (TNBC), lacks such drug targets and conventional cytotoxic chemotherapies often remain the only treatment option. Thus, the development of resistance to cytotoxic therapies has fatal consequences. To assess the involvement of epigenetic mechanisms and their therapeutic potential increasing cytotoxic drug efficiency, we combined high-throughput RNA- and ChIP-sequencing analyses in BLBC cells. Tumor cells surviving chemotherapy upregulated transcriptional programs of epithelial-to-mesenchymal transition (EMT) and stemness. To our surprise, the same cells showed a pronounced reduction of polycomb repressive complex 2 (PRC2) activity via downregulation of its subunits Ezh2 , Suz12, Rbbp7 and Mtf2 . Mechanistically, loss of PRC2 activity leads to the de-repression of a set of genes through an epigenetic switch from repressive H3K27me3 to activating H3K27ac mark at regulatory regions. We identified Nfatc1 as an upregulated gene upon loss of PRC2 activity and directly implicated in the transcriptional changes happening upon survival to chemotherapy. Blocking NFATc1 activation reduced epithelial-to-mesenchymal transition, aggressiveness, and therapy resistance of BLBC cells. Our data demonstrate a previously unknown function of PRC2 maintaining low Nfatc1 expression levels and thereby repressing aggressiveness and therapy resistance in BLBC."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1038/s41419-021-04407-y"],["dc.identifier.pii","4407"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/97731"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-507"],["dc.relation.eissn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.title","Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]