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Nucleic Acids Res. 2014 Apr;42(6):3607-22. doi: 10.1093/nar/gkt1382. Epub 2014 Jan 13.

Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer.

Author information

1
Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA, Ohio State Biochemistry Graduate Program, The Ohio State University, Columbus, OH 43210, USA, Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA, State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China and Medical Sciences Program and Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN 47405, USA.

Abstract

In prostate cancer, androgen receptor (AR) binding and androgen-responsive gene expression are defined by hormone-independent binding patterns of the pioneer factors FoxA1 and GATA2. Insufficient evidence of the mechanisms by which GATA2 contributes to this process precludes complete understanding of a key determinant of tissue-specific AR activity. Our observations suggest that GATA2 facilitates androgen-responsive gene expression by three distinct modes of action. By occupying novel binding sites within the AR gene locus, GATA2 positively regulates AR expression before and after androgen stimulation. Additionally, GATA2 engages AR target gene enhancers prior to hormone stimulation, producing an active and accessible chromatin environment via recruitment of the histone acetyltransferase p300. Finally, GATA2 functions in establishing and/or sustaining basal locus looping by recruiting the Mediator subunit MED1 in the absence of androgen. These mechanisms may contribute to the generally positive role of GATA2 in defining AR genome-wide binding patterns that determine androgen-responsive gene expression profiles. We also find that GATA2 and FoxA1 exhibit both independent and codependent co-occupancy of AR target gene enhancers. Identifying these determinants of AR transcriptional activity may provide a foundation for the development of future prostate cancer therapeutics that target pioneer factor function.

PMID:
24423874
PMCID:
PMC3973339
DOI:
10.1093/nar/gkt1382
[Indexed for MEDLINE]
Free PMC Article

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