TY  - JOUR
A1  - Nagarajan, Sankari
A1  - Bedi, Upasana
A1  - Budida, Anusha
A1  - Hamdan, Feda H.
A1  - Mishra, Vivek Kumar
A1  - Najafova, Zeynab
A1  - Xie, Wanhua
A1  - Alawi, Malik
A1  - Indenbirken, Daniela
A1  - Knapp, Stefan
A1  - Chiang, Cheng-Ming
A1  - Grundhoff, Adam
A1  - Kari, Vijayalakshmi
A1  - Scheel, Christina H.
A1  - Wegwitz, Florian
A1  - Johnsen, Steven A.
T1  - BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells
T2  - Nucleic acids research
N2  - Bromodomain-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.
KW  - phenotype
KW  - signal transduction
KW  - epithelium
KW  - genes
KW  - transcription factor
KW  - rna
KW  - epithelial cells
KW  - epigenetics
KW  - proto-oncogene proteins c-akt
KW  - enhancer of transcription
KW  - tp63 gene
KW  - forkhead box protein o1
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/43938
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-439384
SN  - 1362-4962
SN  - 0305-1048
N1  - The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
VL  - 45
IS  - 6
SP  - 3130
EP  - 3145
PB  - Oxford Univ. Press
CY  - Oxford
ER  -