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dc.contributor.authorPellegrino, Rossella
dc.contributor.authorThavamani, Abhishek
dc.contributor.authorCalvisi, Diego F
dc.contributor.authorBudczies, Jan
dc.contributor.authorNeumann, Ariane
dc.contributor.authorGeffers, Robert
dc.contributor.authorKroemer, Jasmin
dc.contributor.authorGreule, Damaris
dc.contributor.authorSchirmacher, Peter
dc.contributor.authorNordheim, Alfred
dc.contributor.authorLongerich, Thomas
dc.date.accessioned2021-02-12T14:20:14Z
dc.date.available2021-02-12T14:20:14Z
dc.date.issued2021-01-08
dc.identifier.citationCancers (Basel). 2021 Jan 8;13(2):199. doi: 10.3390/cancers13020199.en_US
dc.identifier.issn2072-6694
dc.identifier.pmid33429878
dc.identifier.doi10.3390/cancers13020199
dc.identifier.urihttp://hdl.handle.net/10033/622739
dc.description.abstractDifferent molecular mechanisms support the overexpression of the mouse double minute homolog 4 (MDM4), a functional p53 inhibitor, in human hepatocellular carcinoma (HCC). However, the transcription factors (TFs) leading to its transcriptional upregulation remain unknown. Following promoter and gene expression analyses, putative TFs were investigated using gene-specific siRNAs, cDNAs, luciferase reporter assays, chromatin immunoprecipitation, and XI-011 drug treatment in vitro. Additionally, MDM4 expression was investigated in SRF-VP16iHep transgenic mice. We observed a copy-number-independent upregulation of MDM4 in human HCCs. Serum response factor (SRF), ELK1 and ELK4 were identified as TFs activating MDM4 transcription. While SRF was constitutively detected in TF complexes at the MDM4 promoter, presence of ELK1 and ELK4 was cell-type dependent. Furthermore, MDM4 was upregulated in SRF-VP16-driven murine liver tumors. The pharmacological inhibitor XI-011 exhibited anti-MDM4 activity by downregulating the TFs driving MDM4 transcription, which decreased HCC cell viability and increased apoptosis. In conclusion, SRF drives transcriptional MDM4 upregulation in HCC, acting in concert with either ELK1 or ELK4. The transcriptional regulation of MDM4 may be a promising target for precision oncology of human HCC, as XI-011 treatment exerts anti-MDM4 activity independent from the MDM4 copy number and the p53 status.en_US
dc.language.isoenen_US
dc.publisherMDPIen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectELK1en_US
dc.subjectELK4en_US
dc.subjectERKen_US
dc.subjectETS transcription factorsen_US
dc.subjectHCCen_US
dc.subjectMDM4en_US
dc.subjectMDM4 transcriptional regulationen_US
dc.subjectSRFen_US
dc.subjectXI-011en_US
dc.subjecttumor protein p53en_US
dc.titleSerum Response Factor (SRF) Drives the Transcriptional Upregulation of the MDM4 Oncogene in HCC.en_US
dc.typeArticleen_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalCancersen_US
dc.source.volume13
dc.source.issue2
refterms.dateFOA2021-02-12T14:20:15Z
dc.source.journaltitleCancers
dc.source.countrySwitzerland


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