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BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells

dc.contributor.authorNagarajan, Sankari
dc.contributor.authorBedi, Upasana
dc.contributor.authorBudida, Anusha
dc.contributor.authorHamdan, Feda H.
dc.contributor.authorMishra, Vivek Kumar
dc.contributor.authorNajafova, Zeynab
dc.contributor.authorXie, Wanhua
dc.contributor.authorAlawi, Malik
dc.contributor.authorIndenbirken, Daniela
dc.contributor.authorKnapp, Stefan
dc.contributor.authorChiang, Cheng-Ming
dc.contributor.authorGrundhoff, Adam
dc.contributor.authorKari, Vijayalakshmi
dc.contributor.authorScheel, Christina H.
dc.contributor.authorWegwitz, Florian
dc.contributor.authorJohnsen, Steven A.
dc.date.accessioned2017-10-05T15:10:58Z
dc.date.available2017-10-05T15:10:58Z
dc.date.issued2016
dc.identifier.urihttp://resolver.sub.uni-goettingen.de/purl?gs-1/14764
dc.description.abstractBromodomain-containing protein 4 (BRD4) is a member of the bromo- and extraterminal (BET) domain-containing family of epigenetic readers which is under intensive investigation as a target for anti-tumor therapy. BRD4 plays a central role in promoting the expression of select subsets of genes including many driven by oncogenic transcription factors and signaling pathways. However, the role of BRD4 and the effects of BET inhibitors in non-transformed cells remain mostly unclear. We demonstrate that BRD4 is required for the maintenance of a basal epithelial phenotype by regulating the expression of epithelial-specific genes including TP63 and Grainy Head-like transcription factor-3 (GRHL3) in non-transformed basal-like mammary epithelial cells. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription. Motif analyses of cell context-specific BRD4-enriched regions predicted the involvement of FOXO transcription factors. Consistently, activation of FOXO1 function via inhibition of EGFR-AKT signaling promoted the expression of TP63 and GRHL3. Moreover, activation of Src kinase signaling and FOXO1 inhibition decreased the expression of FOXO/BRD4 target genes. Together, our findings support a function for BRD4 in promoting basal mammary cell epithelial differentiation, at least in part, by regulating FOXO factor function on enhancers to activate TP63 and GRHL3 expression.
dc.rightsopenAccess
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectphenotype; signal transduction; epithelium; genes; transcription factor; rna; epithelial cells; epigenetics; proto-oncogene proteins c-akt; enhancer of transcription; tp63 gene; forkhead box protein; o1
dc.titleBRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells
dc.typejournalArticle
dc.identifier.doi10.1093/nar/gkw1276
dc.relation.pISSN0305-1048
dc.relation.eISSN1362-4962
dc.bibliographicCitation.volume45
dc.bibliographicCitation.issue6
dc.bibliographicCitation.firstPage3130
dc.bibliographicCitation.lastPage3145
dc.identifier.pmid27980063
dc.description.statuspeerReviewed
dc.bibliographicCitation.journalNucleic Acids Research


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