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401F329a37640a178064b020c0 Published online 13 January 2014 Nucleic Acids Research, 2014, Vol. 42, No. 6 3607–3622 doi:10.1093/nar/gkt1382 NAR Breakthrough Article Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer Dayong Wu1,y, Benjamin Sunkel1,2,y, Zhong Chen1, Xiangtao Liu1, Zhenqing Ye3, Qianjin Li1, Cassandra Grenade1, Jingdong Ke1, Chunpeng Zhang1, Hongyan Chen1,4, Kenneth P. Nephew5, Tim H.-M. Huang3, Zhihua Liu4, Victor X. Jin3 and Qianben Wang1,2,* 1Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA, 2Ohio State Biochemistry Graduate Program, The Ohio State University, Columbus, OH 43210, USA, 3Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA, 4State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China and 5Medical Sciences Program and Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN 47405, USA Received August 13, 2013; Revised November 26, 2013; Accepted December 15, 2013 ABSTRACT exhibit both independent and codependent In prostate cancer, androgen receptor (AR) binding co-occupancy of AR target gene enhancers. and androgen-responsive gene expression are Identifying these determinants of AR transcriptional defined by hormone-independent binding patterns of activity may provide a foundation for the develop- the pioneer factors FoxA1 and GATA2. Insufficient ment of future prostate cancer therapeutics that evidence of the mechanisms by which GATA2 con- target pioneer factor function. tributes to this process precludes complete under- standing of a key determinant of tissue-specific AR INTRODUCTION activity. Our observations suggest that GATA2 facili- Androgen signaling mediates diverse and complex func- tates androgen-responsive gene expression by tions throughout the body ranging from skeletal develop- three distinct modes of action. By occupying novel ment and maintenance to spermatogenesis on ligand binding sites within the AR gene locus, GATA2 posi- activation of the androgen receptor (AR) (1). A member tively regulates AR expression before and after of the nuclear hormone receptor family, AR mediates androgen stimulation. Additionally, GATA2 engages androgen-dependent gene expression following release AR target gene enhancers prior to hormone stimu- from cytoplasmic heat-shock proteins, receptor phosphor- lation, producing an active and accessible chroma- ylation and nuclear translocation whereupon AR tin environment via recruitment of the histone homodimers bind to recognition sites within regulatory elements of target genes (2). This mechanism of acetyltransferase p300. Finally, GATA2 functions in hormone-dependent gene expression facilitates the fetal establishing and/or sustaining basal locus looping development of the prostate and regulates maintenance by recruiting the Mediator subunit MED1 in the and normal function of the prostate secretory epithelium absence of androgen. These mechanisms may con- (1,3). In androgen-dependent prostate cancer (ADPC), tribute to the generally positive role of GATA2 in androgen-stimulated AR function plays a vital role defining AR genome-wide binding patterns that in the aberrant proliferation of epithelial cells, thus determine androgen-responsive gene expression androgen deprivation therapy (ADT) precipitates profiles. We also find that GATA2 and FoxA1 marked disease regression (3,4). As is too often the case *To whom correspondence should be addressed. Tel: +1 614 247 1609; Fax: +1 614 688 4181; Email: [email protected] yThese authors contributed equally to the paper as first authors. ß The Author(s) 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0/), 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 [email protected] 3608 Nucleic Acids Research, 2014, Vol. 42, No. 6 however, reestablished AR activity leads to ADT resist- While GATA family proteins have long since been ance, marking the fatal progression to castration resistant identified as putative pioneer factors acting in concert prostate cancer (CRPC) (5–7). How tissue-, cell type-, and with FOX proteins in establishing temporal gene expres- disease stage-specific patterns of androgen-stimulated sion patterns required for fetal liver development (28,29), gene expression are generated is an area of considerable progress in understanding GATA pioneer function in NR- research focus, and a complete picture of the activities driven cancers has been largely limited to ER activity. determining this specificity is required for our understand- GATA3 expression patterns positively correlate with ing of androgen-driven prostate cancer progression both ER and FoxA1 in the developing, mature and can- and for the rational design of potent prostate cancer cerous mammary epithelium, and are in fact necessary therapeutics. for determining hormone-responsive gene expression and In nuclear receptor (NR)-regulated gene transcription, breast cancer cell proliferation (30–34). As stated, prostate pioneer factor function has been studied extensively, cancer-specific AR binding sites are also significantly providing information on the manner in which tissue- enriched in GATA motifs, and GATA2, overexpressed specific, hormone-responsive gene expression is controlled in high-risk prostate cancer, has been shown to play an (8–10). Pioneer factors are characterized by their ability to essential role in productive AR-chromatin binding result- engage compact chromatin, initialize local chromatin ing in androgen-responsive gene expression (12,16,35). decondensation and provide an environment amenable Given existing evidence for the central role of GATA to the recruitment of transcription factors and activation family members in defining transcription factor activity, of transcription (10). Their role in determining NR target the demonstrated function of GATA factors in facilitating gene expression was suggested on analysis of common hormone-dependent gene expression, and the dearth of DNA sequence motifs enriched within genome-wide NR information on the mechanism by which GATA proteins binding sites identified using chromatin immunopre- contribute functionally to NR-transcriptional regulation, cipitation combined with tiled oligonucleotide micro- further analyses are needed to elucidate the means by arrays (ChIP-on-chip) or high-throughput sequencing which GATA pioneer factors function in hormone- technology (ChIP-seq) (11–15). Two key pioneer factors related cancers. emerged from complementary analyses in distinct In the present work, we focus specifically on the role of hormone-related cancers, breast and prostate, driven by GATA2 in recruiting AR to distal enhancers elements estrogen receptor (ER) and AR transcriptional activity, of androgen-responsive AR target genes in androgen- respectively. Significantly enriched within ER and AR responsive prostate cancer cell lines. We provide evidence that GATA2 acts at multiple levels to contribute binding sites were motifs recognized by the Forkhead positively to AR transcriptional activity by enhancing AR box (FOX) and GATA pioneer transcription factor expression itself, facilitating AR-enhancer binding by families (10,12,13,16,17). establishing an accessible local chromatin environment, FOX proteins, specifically the FOXA subclass, have at- and enhancing AR target gene expression through in- tracted considerable attention for their capacity to impact volvement in the formation and maintenance of regulatory local chromatin architecture, their essential role in priming chromatin loops between AR-bound distal enhancers for temporal patterns of gene expression observed in early and AR target gene promoters. These mechanisms may organogenesis and their influence over tissue-specific account for the generally positive role of GATA2 in patterns of NR target gene expression, of particular defining global AR binding that regulates AR target interest in hormone-related cancers (9,10,18,19). In par- gene expression. Additionally, we reveal a complex rela- ticular, FoxA1, expressed alongside ER and AR in the tionship between FoxA1 and GATA2 in mediating AR developing and mature mammary and prostate ductal expression and in site-specific AR recruitment facilitating epithelia, respectively (20–23), has been shown to contrib- AR target gene expression. ute significantly to maintaining the oncogenic functions of these nuclear receptors in both treatment-sensitive and -resistant breast and prostate cancers (11,16). While the MATERIALS AND METHODS role of FoxA1 in ER-positive breast cancers appears to be Cell culture the positive regulation of ER-chromatin binding, resulting in canonical and noncanonical ligand-dependent ER The prostate cancer cell line LNCaP was purchased from target gene expression and breast cancer cell proliferation the American Type Culture Collection (ATCC), and (11,24), a more complex relationship between AR and C4-2B cells were purchased from ViroMed Laboratories. FoxA1 exists in prostate cancer. Initial studies described These cells were maintained
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