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

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

doi:10.1093/nar/gkt1382

Cited by 121 publications

(147 citation statements)

References 67 publications

(101 reference statements)

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“…Using ChIP-seq, GATA2 was found to bind to a regulatory element 5.5 kb upstream of the TSS of the AR gene and enhanced transcription, while treatment of prostate cells with an AR agonist led to repression of both GATA2 and AR mRNA . In addition, a GATA2 binding site downstream of the TSS at +762 has also been correlated with positive regulation of the AR gene (Wu et al 2014) (Figure 2). …”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 93%

Tissue control of androgen action: The ups and downs of androgen receptor expression

Hunter

Hay

Esswein

et al. 2018

Molecular and Cellular Endocrinology

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Please cite this article as: Hunter, I., Hay, C.W., Esswein, B., Watt, K., McEwan, I.J., Tissue control of androgen action: The ups and downs of androgen receptor expression, Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 93%

Tissue control of androgen action: The ups and downs of androgen receptor expression

Hunter

Hay

Esswein

et al. 2018

Molecular and Cellular Endocrinology

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“…ChIP-on-chip analysis revealed that the GATAbinding motif is enriched in the AR-binding chromatin regions in LNCaP cells (23). GATA2 has been reported to facilitate androgen-responsive gene expression (24) and to promote cell migration, tissue invasion, and metastasis (25). It has been reported that GATA2 can directly regulate AR gene expression in a stable LNCaP cell line with doxycycline-inducible GATA2 (26).…”

Section: Significancementioning

confidence: 99%

GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex

Lanz

Fiskus

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

104

157

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The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both fulllength and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a firstin-field approach to target AR expression and function and improve outcomes in CRPC.prostate cancer | small molecule inhibitor | AR signaling | GATA2 | steroid receptor coactivator

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“…We hypothesized that the above-observed 9q22 enhancer elements might regulate FOXE1 and PTCSC2 expression by enhancing their transcription through direct interaction. In an effort to demonstrate this physical interaction, we used the chromosome conformation capture (3C) assay and utilized the KTC-1 cell line for the initial analyses (26). We evaluated the interactions between fragments across the ∼33-kb LD block and the upstream regions of FOXE1 and PTCSC2.…”

Section: Physical Interaction Between the Enhancers And The Promotermentioning

confidence: 99%

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

Liyanarachchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we finemapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.thyroid cancer | genetic susceptibility | long-range enhancer | functional variants | SNP rs965513 P apillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for >80% of all thyroid malignancy. It is estimated that 62,450 individuals in the United States will be diagnosed with thyroid cancer in 2015 (www.cancer. org/Research/CancerFactsFigures/index). Although PTC is clearly influenced by both genetic and environmental factors, genetic predisposition plays a major role as evidenced by case-control studies (1-3).Genome-wide association studies (GWASs) have linked SNP rs965513 in 9q22 to thyroid cancer, mainly PTC. The odds ratio (OR) for this SNP is as high as ∼1.8 (4). The association between rs965513 and thyroid cancer risk has been independently confirmed in different populations (5-11). The association was also observed in familial PTC and in patients with radiation-induced PTC (12-15). SNP rs965513 resides ∼60 kb upstream of forkhead box E1 (FOXE1) (also known as thyroid transcription factor 2), a critical transcription factor (TF) in thyroid development, differentiation, and function (16)(17)(18)(19). It has been repeatedly proposed that FOXE1 is involved in the tumorigenesis of PTC (11,19,20). A DNA variant (rs1867277) in the promoter region of FOXE1 was reported as a functional variant involved in transcriptional regulation of FOXE1 (19). However, these studi...

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

Cited by 121 publications

References 67 publications

Tissue control of androgen action: The ups and downs of androgen receptor expression

Tissue control of androgen action: The ups and downs of androgen receptor expression

GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

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