Wegwitz, Florian

[["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.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.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"]]

[["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Cell Death & Disease"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Prokakis, Evangelos"],["dc.contributor.author","Pejkovska, Anastasija"],["dc.contributor.author","Kosinsky, Robyn Laura"],["dc.contributor.author","Glatzel, Markus"],["dc.contributor.author","Pantel, Klaus"],["dc.contributor.author","Wikman, Harriet"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2021-04-14T08:31:50Z"],["dc.date.available","2021-04-14T08:31:50Z"],["dc.date.issued","2020"],["dc.description.sponsorship","Open-Access-Finanzierung durch die Universitätsmedizin Göttingen 2021"],["dc.identifier.doi","10.1038/s41419-020-03081-w"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83728"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation.eissn","2041-4889"],["dc.title","The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","98"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Clinical Epigenetics"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Schneider, Deborah"],["dc.contributor.author","Chua, Robert L"],["dc.contributor.author","Molitor, Nicole"],["dc.contributor.author","Hamdan, Feda H"],["dc.contributor.author","Rettenmeier, Eva M"],["dc.contributor.author","Prokakis, Evangelos"],["dc.contributor.author","Mishra, Vivek K"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Johnsen, Steven A"],["dc.contributor.author","Kosinsky, Robyn L"],["dc.date.accessioned","2019-07-09T11:51:58Z"],["dc.date.available","2019-07-09T11:51:58Z"],["dc.date.issued","2019"],["dc.description.abstract","Abstract Background Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide, and deciphering underlying molecular mechanism is essential. The loss of monoubiquitinated histone H2B (H2Bub1) was correlated with poor prognosis of CRC patients and, accordingly, H2Bub1 was suggested as a tumor-suppressive mark. Surprisingly, our previous work revealed that the H2B ubiquitin ligase RING finger protein 40 (RNF40) might exert tumor-promoting functions. Here, we investigated the effect of RNF40 loss on tumorigenic features of CRC cells and their survival in vitro. Methods We evaluated the effects of RNF40 depletion in several human CRC cell lines in vitro. To evaluate cell cycle progression, cells were stained with propidium iodide and analyzed by flow cytometry. In addition, to assess apoptosis rates, caspase 3/7 activity was assessed in a Celigo® S-based measurement and, additionally, an Annexin V assay was performed. Genomic occupancy of H2Bub1, H3K79me3, and H3K27ac was determined by chromatin immunoprecipitation. Transcriptome-wide effects of RNF40 loss were evaluated based on mRNA-seq results, qRT-PCR, and Western blot. To rescue apoptosis-related effects, cells were treated with Z-VAD-FMK. Results Human CRC cell lines displayed decreased cell numbers in vitro after RNF40 depletion. While the differences in confluence were not mediated by changes in cell cycle progression, we discovered highly increased apoptosis rates after RNF40 knockdown due to elevated caspase 3/7 activity. This effect can be explained by reduced mRNA levels of anti-apoptotic and upregulation of pro-apoptotic BCL2 family members. Moreover, the direct occupancy of the RNF40-mediated H2B monoubiquitination was observed in the transcribed region of anti-apoptotic genes. Caspase inhibition by Z-VAD-FMK treatment rescued apoptosis in RNF40-depleted cells. However, knockdown cells still displayed decreased tumorigenic features despite the absence of apoptosis. Conclusions Our findings reveal that RNF40 is essential for maintaining tumorigenic features of CRC cells in vitro by controlling the expression of genes encoding central apoptotic regulators."],["dc.identifier.doi","10.1186/s13148-019-0698-x"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16251"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/60054"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","BioMed Central"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The E3 ubiquitin ligase RNF40 suppresses apoptosis in colorectal cancer cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]