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

Dayong Wu, Benjamin Sunkel, Zhong Chen, Xiangtao Liu, Zhenqing Ye, Qianjin Li, Cassandra Grenade, Jingdong Ke, Chunpeng Zhang, Hongyan Chen, Kenneth P. Nephew, Tim H.M. Huang, Zhihua Liu, Victor X. Jin, Qianben Wang

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3607-3622
Number of pages16
JournalNucleic acids research
Volume42
Issue number6
DOIs
StatePublished - Apr 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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