Publications by authors named "Qianben Wang"

55 Publications

A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

Department of Pathology, Duke University School of Medicine, Durham, NC 27710;

Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression.
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http://dx.doi.org/10.1073/pnas.2012748118DOI Listing
March 2021

The oncogenomic function of androgen receptor in esophageal squamous cell carcinoma is directed by GATA3.

Cell Res 2021 Mar 2;31(3):362-365. Epub 2020 Nov 2.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

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http://dx.doi.org/10.1038/s41422-020-00428-yDOI Listing
March 2021

Prostate Cancer Cell Phenotypes Remain Stable Following PDE5 Inhibition in the Clinically Relevant Range.

Transl Oncol 2020 Sep 23;13(9):100797. Epub 2020 May 23.

Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address:

Widespread cGMP-specific phosphodiesterase 5 (PDE5) inhibitor use in male reproductive health and particularly in prostate cancer patients following surgery has generated interest in how these drugs affect the ability of residual tumor cells to proliferate, migrate, and form recurrent colonies. Prostate cancer cell lines were treated with PDE5 inhibitors at clinically relevant concentrations. Proliferation, colony formation, and migration phenotypes remained stable even when cells were co-treated with a stimulator of cGMP synthesis that facilitated cGMP accumulation upon PDE5 inhibition. Surprisingly, supraclinical concentrations of PDE5 inhibitor counteracted proliferation, colony formation, and migration of prostate cancer cell models. These findings provide tumor cell-autonomous evidence in support of the field's predominant view that PDE5 inhibitors are safe adjuvant agents to promote functional recovery of normal tissue after prostatectomy, but do not rule out potential cancer-promoting effects of PDE5 inhibitors in the more complex environment of the prostate.
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http://dx.doi.org/10.1016/j.tranon.2020.100797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248418PMC
September 2020

Shaping Chromatin States in Prostate Cancer by Pioneer Transcription Factors.

Cancer Res 2020 06 24;80(12):2427-2436. Epub 2020 Feb 24.

Department of Pathology and Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina.

The androgen receptor (AR) is a critical therapeutic target in prostate cancer that responds to antagonists in primary disease, but inevitably becomes reactivated, signaling onset of the lethal castration-resistant prostate cancer (CRPC) stage. Epigenomic investigation of the chromatin environment and interacting partners required for AR transcriptional activity has uncovered three pioneer factors that open up chromatin and facilitate AR-driven transcriptional programs. FOXA1, HOXB13, and GATA2 are required for normal AR transcription in prostate epithelial development and for oncogenic AR transcription during prostate carcinogenesis. AR signaling is dependent upon these three pioneer factors both before and after the clinical transition from treatable androgen-dependent disease to untreatable CRPC. Agents targeting their respective DNA binding or downstream chromatin-remodeling events have shown promise in preclinical studies of CRPC. AR-independent functions of FOXA1, HOXB13, and GATA2 are emerging as well. While all three pioneer factors exert effects that promote carcinogenesis, some of their functions may inhibit certain stages of prostate cancer progression. In all, these pioneer factors represent some of the most promising potential therapeutic targets to emerge thus far from the study of the prostate cancer epigenome.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299826PMC
June 2020

Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.

Sci Transl Med 2019 12;11(521)

Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR luminal tumor cells and AR neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
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http://dx.doi.org/10.1126/scitranslmed.aax0428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238624PMC
December 2019

Alternative polyadenylation of mRNA and its role in cancer.

Genes Dis 2021 Jan 25;8(1):61-72. Epub 2019 Oct 25.

Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.

Alternative polyadenylation (APA) is a molecular process that generates diversity at the 3' end of RNA polymerase II transcripts from over 60% of human genes. APA is derived from the existence of multiple polyadenylation signals (PAS) within the same transcript, and results in the differential inclusion of sequence information at the 3' end. While APA can occur between two PASs allowing for generation of transcripts with distinct coding potential from a single gene, most APA occurs within the untranslated region (3'UTR) and changes the length and content of these non-coding sequences. APA within the 3'UTR can have tremendous impact on its regulatory potential of the mRNA through a variety of mechanisms, and indeed this layer of gene expression regulation has profound impact on processes vital to cell growth and development. Recent studies have particularly highlighted the importance of APA dysregulation in cancer onset and progression. Here, we review the current knowledge of APA and its impacts on mRNA stability, translation, localization and protein localization. We also discuss the implications of APA dysregulation in cancer research and therapy.
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http://dx.doi.org/10.1016/j.gendis.2019.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859462PMC
January 2021

Molecular determinants for enzalutamide-induced transcription in prostate cancer.

Nucleic Acids Res 2019 11;47(19):10104-10114

Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.

Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 globally directs enzalutamide-induced transcription by facilitating AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.
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http://dx.doi.org/10.1093/nar/gkz790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821169PMC
November 2019

Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.

Oncotarget 2018 Jul 27;9(58):31214-31230. Epub 2018 Jul 27.

Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.

Mutation of the gene occurs in a high percentage of colorectal tumors and is a central event driving tumor initiation in the large intestine. The APC protein performs multiple tumor suppressor functions including negative regulation of the canonical WNT signaling pathway by both cytoplasmic and nuclear mechanisms. Published reports that APC interacts with β-catenin in the chromatin fraction to repress WNT-activated targets have raised the possibility that chromatin-associated APC participates more broadly in mechanisms of transcriptional control. This screening study has used chromatin immunoprecipitation and next-generation sequencing to identify APC-associated genomic regions in colon cancer cell lines. Initial target selection was performed by comparison and statistical analysis of 3,985 genomic regions associated with the APC protein to whole transcriptome sequencing data from APC-deficient and APC-wild-type colon cancer cells, and two types of murine colon adenomas characterized by activated Wnt signaling. 289 transcripts altered in expression following APC loss in human cells were linked to APC-associated genomic regions. High-confidence targets additionally validated in mouse adenomas included 16 increased and 9 decreased in expression following APC loss, indicating that chromatin-associated APC may antagonize canonical WNT signaling at both WNT-activated and WNT-repressed targets. Motif analysis and comparison to ChIP-seq datasets for other transcription factors identified a prevalence of binding sites for the TCF7L2 and AP-1 transcription factors in APC-associated genomic regions. Our results indicate that canonical WNT signaling can collaborate with or antagonize the AP-1 transcription factor to fine-tune the expression of shared target genes in the colorectal epithelium. Future therapeutic strategies for APC-deficient colorectal cancers might be expanded to include agents targeting the AP-1 pathway.
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http://dx.doi.org/10.18632/oncotarget.25781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101278PMC
July 2018

Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis.

Nucleic Acids Res 2018 09;46(17):8832-8847

School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we show EZH2 acts antagonistically to AKT signaling in maintaining H3K27 methylome through epigenetic silencing of IGFBP4. ChIP-seq revealed enrichment of Ezh2/H3K27me3 at silenced loci in HBx-transgenic mouse-derived HCCs, including Igfbp4 whose down-regulation significantly correlated with EZH2 overexpression and poor survivals of HCC patients. Functional characterizations demonstrated potent growth- and invasion-suppressive functions of IGFBP4, which was associated with transcriptomic alterations leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 stimulated AKT/EZH2 phosphorylation to abrogate H3K27me3-mediated silencing, forming a reciprocal feedback loop that suppressed core transcription factor networks (FOXA1/HNF1A/HNF4A/KLF9/NR1H4) for normal liver homeostasis. Consequently, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was vulnerable to pharmacological inhibition of EZH2, but not AKT. Our study unveils chromatin regulation of a novel liver tumor suppressor IGFBP4, which constitutes an AKT-EZH2 reciprocal loop in driving H3K27me3-mediated epigenetic reprogramming. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.
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http://dx.doi.org/10.1093/nar/gky589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158508PMC
September 2018

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13.

Proc Natl Acad Sci U S A 2018 06 29;115(26):6810-6815. Epub 2018 May 29.

Department of Pathology, Duke University School of Medicine, Durham, NC 27710;

The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7-driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7-driven prostate tumors.
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http://dx.doi.org/10.1073/pnas.1718811115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042123PMC
June 2018

Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle-Related Transcription and Attenuated Androgen Response.

Cancer Res 2018 02 12;78(4):853-864. Epub 2017 Dec 12.

Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell-cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G-M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle-related genes (, and ) and decreased dependence upon androgen receptor signaling. analysis of RNA-seq data from The Cancer Genome Atlas further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen deprivation therapies and reveals characteristics of subpopulations resistant to this treatment. Illustrating the challenge in treating cancers with targeted drugs, which by selecting for drug resistance can drive metastatic progression, this study characterized the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, defining the character or minor subpopulations of androgen-independent cells that are poised for clonal selection after androgen-deprivation therapy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983359PMC
February 2018

Genome-wide analysis reveals positional-nucleosome-oriented binding pattern of pioneer factor FOXA1.

Nucleic Acids Res 2016 09 25;44(16):7540-54. Epub 2016 Jul 25.

Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX 78229, USA

The compaction of nucleosomal structures creates a barrier for DNA-binding transcription factors (TFs) to access their cognate cis-regulatory elements. Pioneer factors (PFs) such as FOXA1 are able to directly access these cis-targets within compact chromatin. However, how these PFs interplay with nucleosomes remains to be elucidated, and is critical for us to understand the underlying mechanism of gene regulation. Here, we have conducted a computational analysis on a strand-specific paired-end ChIP-exo (termed as ChIP-ePENS) data of FOXA1 in LNCaP cells by our novel algorithm ePEST. We find that FOXA1 chromatin binding occurs via four distinct border modes (or footprint boundary patterns), with a preferential footprint boundary patterns relative to FOXA1 motif orientation. In addition, from this analysis three fundamental nucleotide positions (oG, oS and oH) emerged as major determinants for blocking exo-digestion and forming these four distinct border modes. By integrating histone MNase-seq data, we found an astonishingly consistent, 'well-positioned' configuration occurs between FOXA1 motifs and dyads of nucleosomes genome-wide. We further performed ChIP-seq of eight chromatin remodelers and found an increased occupancy of these remodelers on FOXA1 motifs for all four border modes (or footprint boundary patterns), indicating the full occupancy of FOXA1 complex on the three blocking sites (oG, oS and oH) likely produces an active regulatory status with well-positioned phasing for protein binding events. Together, our results suggest a positional-nucleosome-oriented accessing model for PFs seeking target motifs, in which FOXA1 can examine each underlying DNA nucleotide and is able to sense all potential motifs regardless of whether they face inward or outward from histone octamers along the DNA helix axis.
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http://dx.doi.org/10.1093/nar/gkw659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027512PMC
September 2016

Transcriptome regulation and chromatin occupancy by E2F3 and MYC in mice.

Sci Data 2016 Feb 16;3:160008. Epub 2016 Feb 16.

Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, Columbus, Ohio 43210, USA.

E2F3 and MYC are transcription factors that control cellular proliferation. To study their mechanism of action in the context of a regenerating tissue, we isolated both proliferating (crypts) and non-dividing (villi) cells from wild-type and Rb depleted small intestines of mice and performed ChIP-exo-seq (chromatin immunoprecipitation combined with lambda exonuclease digestion followed by high-throughput sequencing). The genome-wide chromatin occupancy of E2F3 and MYC was determined by mapping sequence reads to the genome and predicting preferred binding sites (peaks). Binding sites could be accurately identified within small regions of only 24 bp-28 bp long, highlighting the precision to which binding peaks can be identified by ChIP-exo-seq. Forty randomly selected E2F3- and MYC-specific binding sites were validated by ChIP-PCR. In addition, we also presented gene expression data sets from wild type, Rb-, E2f3- and Myc-depleted crypts and villi within this manuscript. These represent comprehensive and validated datasets that can be integrated to identify putative direct targets of E2F3 and MYC involved in the control of cellular proliferation in normal and Rb-deficient small intestines.
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http://dx.doi.org/10.1038/sdata.2016.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755127PMC
February 2016

Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co-regulation as a predictor of prostate cancer recurrence.

Nucleic Acids Res 2016 05 6;44(9):4105-22. Epub 2016 Jan 6.

Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA

Identifying prostate cancer-driving transcription factors (TFs) in addition to the androgen receptor promises to improve our ability to effectively diagnose and treat this disease. We employed an integrative genomics analysis of master TFs CREB1 and FoxA1 in androgen-dependent prostate cancer (ADPC) and castration-resistant prostate cancer (CRPC) cell lines, primary prostate cancer tissues and circulating tumor cells (CTCs) to investigate their role in defining prostate cancer gene expression profiles. Combining genome-wide binding site and gene expression profiles we define CREB1 as a critical driver of pro-survival, cell cycle and metabolic transcription programs. We show that CREB1 and FoxA1 co-localize and mutually influence each other's binding to define disease-driving transcription profiles associated with advanced prostate cancer. Gene expression analysis in human prostate cancer samples found that CREB1/FoxA1 target gene panels predict prostate cancer recurrence. Finally, we showed that this signaling pathway is sensitive to compounds that inhibit the transcription co-regulatory factor MED1. These findings not only reveal a novel, global transcriptional co-regulatory function of CREB1 and FoxA1, but also suggest CREB1/FoxA1 signaling is a targetable driver of prostate cancer progression and serves as a biomarker of poor clinical outcomes.
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http://dx.doi.org/10.1093/nar/gkv1528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872073PMC
May 2016

Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer.

Nat Commun 2015 Sep 16;6:8323. Epub 2015 Sep 16.

Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.

Glucocorticoids (GCs) have been widely used as coadjuvants in the treatment of solid tumours, but GC treatment may be associated with poor pharmacotherapeutic response or prognosis. The genomic action of GC in these tumours is largely unknown. Here we find that dexamethasone (Dex, a synthetic GC)-regulated genes in triple-negative breast cancer (TNBC) cells are associated with drug resistance. Importantly, these GC-regulated genes are aberrantly expressed in TNBC patients and are associated with unfavourable clinical outcomes. Interestingly, in TNBC cells, Compound A (CpdA, a selective GR modulator) only regulates a small number of genes not involved in carcinogenesis and therapy resistance. Mechanistic studies using a ChIP-exo approach reveal that Dex- but not CpdA-liganded glucocorticoid receptor (GR) binds to a single glucocorticoid response element (GRE), which drives the expression of pro-tumorigenic genes. Our data suggest that development of safe coadjuvant therapy should consider the distinct genomic function between Dex- and CpdA-liganded GR.
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http://dx.doi.org/10.1038/ncomms9323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573460PMC
September 2015

Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes.

Nat Genet 2015 Oct 24;47(10):1149-57. Epub 2015 Aug 24.

Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.

Tumor suppressors are mostly defined by inactivating mutations in tumors, yet little is known about their epigenetic features in normal cells. Through integrative analysis of 1,134 genome-wide epigenetic profiles, mutations from >8,200 tumor-normal pairs and our experimental data from clinical samples, we discovered broad peaks for trimethylation of histone H3 at lysine 4 (H3K4me3; wider than 4 kb) as the first epigenetic signature for tumor suppressors in normal cells. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity, which together lead to exceptionally high gene expression, and is distinct from other broad epigenetic features, such as super-enhancers. Genes with broad H3K4me3 peaks conserved across normal cells may represent pan-cancer tumor suppressors, such as TP53 and PTEN, whereas genes with cell type-specific broad H3K4me3 peaks may represent cell identity genes and cell type-specific tumor suppressors. Furthermore, widespread shortening of broad H3K4me3 peaks in cancers is associated with repression of tumor suppressors. Thus, the broad H3K4me3 epigenetic signature provides mutation-independent information for the discovery and characterization of new tumor suppressors.
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http://dx.doi.org/10.1038/ng.3385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780747PMC
October 2015

Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles.

Nat Cell Biol 2015 Aug 20;17(8):1036-48. Epub 2015 Jul 20.

1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.

Robust mechanisms to control cell proliferation have evolved to maintain the integrity of organ architecture. Here, we investigated how two critical proliferative pathways, Myc and E2f, are integrated to control cell cycles in normal and Rb-deficient cells using a murine intestinal model. We show that Myc and E2f1-3 have little impact on normal G1-S transitions. Instead, they synergistically control an S-G2 transcriptional program required for normal cell divisions and maintaining crypt-villus integrity. Surprisingly, Rb deficiency results in the Myc-dependent accumulation of E2f3 protein and chromatin repositioning of both Myc and E2f3, leading to the 'super activation' of a G1-S transcriptional program, ectopic S phase entry and rampant cell proliferation. These findings reveal that Rb-deficient cells hijack and redeploy Myc and E2f3 from an S-G2 program essential for normal cell cycles to a G1-S program that re-engages ectopic cell cycles, exposing an unanticipated addiction of Rb-null cells on Myc.
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http://dx.doi.org/10.1038/ncb3210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526313PMC
August 2015

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

Proc Natl Acad Sci U S A 2015 May 27;112(19):6128-33. Epub 2015 Apr 27.

Human Cancer Genetics Program and Department of Molecular Virology, Immunology, and Medical Genetics,

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 fine-mapped 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.
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http://dx.doi.org/10.1073/pnas.1506255112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434723PMC
May 2015

Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer.

EMBO J 2015 Feb 22;34(4):502-16. Epub 2014 Dec 22.

Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA

Human transcription factors recognize specific DNA sequence motifs to regulate transcription. It is unknown whether a single transcription factor is able to bind to distinctly different motifs on chromatin, and if so, what determines the usage of specific motifs. By using a motif-resolution chromatin immunoprecipitation-exonuclease (ChIP-exo) approach, we find that agonist-liganded human androgen receptor (AR) and antagonist-liganded AR bind to two distinctly different motifs, leading to distinct transcriptional outcomes in prostate cancer cells. Further analysis on clinical prostate tissues reveals that the binding of AR to these two distinct motifs is involved in prostate carcinogenesis. Together, these results suggest that unique ligands may switch DNA motifs recognized by ligand-dependent transcription factors in vivo. Our findings also provide a broad mechanistic foundation for understanding ligand-specific induction of gene expression profiles.
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http://dx.doi.org/10.15252/embj.201490306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331004PMC
February 2015

Knockdown of PRKAR1A, the gene responsible for Carney complex, interferes with differentiation in osteoblastic cells.

Mol Endocrinol 2014 Mar 7;28(3):295-307. Epub 2014 Feb 7.

Departments of Molecular, Virology, Immunology, and Medical Genetics (M.Z., P.K.M., L.S.K.) and Molecular and Cellular Biochemistry (D.W., Q.W.) and Division of Endocrinology, Diabetes, and Metabolism (L.S.K.), The Ohio State University, Columbus, Ohio 43210.

PRKAR1A is the gene encoding the type 1A regulatory subunit of protein kinase A, and it is the cause of the inherited human tumor syndrome Carney complex. Data from our laboratory has demonstrated that Prkar1a loss causes tumors in multiple cell lineages, including neural crest cells and osteoblasts. We have proposed that one mechanism by which tumorigenesis occurs is through the failure of terminal differentiation. In the present study, we directly test the effects of Prkar1a reduction on osteogenic differentiation in mouse and human cells in vitro. We found that Prkar1a levels noticeably increased during osteoblastic differentiation, indicating a positive correlation between the expression of Prkar1a and osteogenic potential. To validate this hypothesis, we generated stable Prkar1a knockdown in both mouse and human cells. These cells displayed significantly suppressed bone nodule formation and decreased expression of osteoblast markers such as osteocalcin and osteopontin. These observations imply that the antiosteogenic effect of Prkar1a ablation is not species or cell line specific. Furthermore, because Runt-related transcription factor-2 (Runx2) is a key mediator of osteoblast differentiation, we reasoned that the function of this transcription factor may be inhibited by Prkar1a knockdown. Chromatin immunoprecipitation and luciferase assays demonstrated that Prkar1a ablation repressed DNA binding and function of Runx2 at its target genes. Additionally, we determined that this effect is likely due to reductions in the Runx2-cooperating transcription factors forkhead box O1 and activating transcription factor 4. Taken together, this study provides direct evidence that ablation of Prkar1a interferes with signaling pathways necessary for osteoblast differentiation.
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http://dx.doi.org/10.1210/me.2013-1152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938543PMC
March 2014

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

Nucleic Acids Res 2014 Apr 13;42(6):3607-22. Epub 2014 Jan 13.

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.

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.
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http://dx.doi.org/10.1093/nar/gkt1382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973339PMC
April 2014

Computational analysis reveals a correlation of exon-skipping events with splicing, transcription and epigenetic factors.

Nucleic Acids Res 2014 Mar 24;42(5):2856-69. Epub 2013 Dec 24.

Departments of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA, Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Rockville, MD 20852, USA and Deparment of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Alternative splicing (AS), in higher eukaryotes, is one of the mechanisms of post-transcriptional regulation that generate multiple transcripts from the same gene. One particular mode of AS is the skipping event where an exon may be alternatively excluded or constitutively included in the resulting mature mRNA. Both transcript isoforms from this skipping event site, i.e. in which the exon is either included (inclusion isoform) or excluded (skipping isoform), are typically present in one cell, and maintain a subtle balance that is vital to cellular function and dynamics. However, how the prevailing conditions dictate which isoform is expressed and what biological factors might influence the regulation of this process remain areas requiring further exploration. In this study, we have developed a novel computational method, graph-based exon-skipping scanner (GESS), for de novo detection of skipping event sites from raw RNA-seq reads without prior knowledge of gene annotations, as well as for determining the dominant isoform generated from such sites. We have applied our method to publicly available RNA-seq data in GM12878 and K562 cells from the ENCODE consortium and experimentally validated several skipping site predictions by RT-PCR. Furthermore, we integrated other sequencing-based genomic data to investigate the impact of splicing activities, transcription factors (TFs) and epigenetic histone modifications on splicing outcomes. Our computational analysis found that splice sites within the skipping-isoform-dominated group (SIDG) tended to exhibit weaker MaxEntScan-calculated splice site strength around middle, 'skipping', exons compared to those in the inclusion-isoform-dominated group (IIDG). We further showed the positional preference pattern of splicing factors, characterized by enrichment in the intronic splice sites immediately bordering middle exons. Finally, our analysis suggested that different epigenetic factors may introduce a variable obstacle in the process of exon-intron boundary establishment leading to skipping events.
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http://dx.doi.org/10.1093/nar/gkt1338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950716PMC
March 2014

S100A14: novel modulator of terminal differentiation in esophageal cancer.

Mol Cancer Res 2013 Dec 9;11(12):1542-53. Epub 2013 Oct 9.

State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.

Unlabelled: Aberrant keratinocyte differentiation is a key mechanism in the initiation of cancer. Because activities regulating differentiation exhibit altered or reduced capacity in esophageal cancer cells, it is vital to pinpoint those genes that control epidermal proliferation and terminal differentiation to better understand esophageal carcinogenesis. S100A14 is a member of the S100 calcium-binding protein family and has been suggested to be involved in cell proliferation, apoptosis, and invasion. The present study used immunohistochemistry analysis of S100A14 in clinical specimens of esophageal squamous cell carcinoma (ESCC) to show that decreased S100A14 is strongly correlated with poor differentiation. Furthermore, both mRNA and protein expression of S100A14 was drastically increased upon 12-O-tetra-decanoylphorbol-13-acetate (TPA) and calcium-induced esophageal cancer cell differentiation. Overexpression of S100A14 resulted in a G1-phase cell cycle arrest and promoted calcium-inhibited cell growth. Conversely, decreasing S100A14 expression significantly promoted G1-S transition and prevented the morphologic changes associated with calcium-induced cell differentiation. Molecular investigation demonstrated that S100A14 altered the calcium-induced expression of late markers of differentiation, with the most prominent effect on involucrin (IVL) and filaggrin (FLG). Finally, it was determined that S100A14 is transcriptionally regulated by JunB and that S100A14 and JunB status significantly correlated in ESCC tissue. In summary, these data demonstrate that S100A14 is transcriptionally regulated by JunB and involved in ESCC cell differentiation.

Implications: This study further differentiates the molecular mechanism controlling the development and progression of esophageal cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-13-0317DOI Listing
December 2013

Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.

PLoS One 2013 14;8(5):e61920. Epub 2013 May 14.

Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, the Ohio State University, Columbus, Ohio, USA.

Thyroid cancer shows high heritability but causative genes remain largely unknown. According to a common hypothesis the genetic predisposition to thyroid cancer is highly heterogeneous; being in part due to many different rare alleles. Here we used linkage analysis and targeted deep sequencing to detect a novel single-nucleotide mutation in chromosome 4q32 (4q32A>C) in a large pedigree displaying non-medullary thyroid carcinoma (NMTC). This mutation is generally ultra-rare; it was not found in 38 NMTC families, in 2676 sporadic NMTC cases or 2470 controls. The mutation is located in a long-range enhancer element whose ability to bind the transcription factors POU2F and YY1 is significantly impaired, with decreased activity in the presence of the C- allele compared with the wild type A-allele. An enhancer RNA (eRNA) is transcribed in thyroid tissue from this region and is greatly downregulated in NMTC tumors. We suggest that this is an example of an ultra-rare mutation predisposing to thyroid cancer with high penetrance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061920PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653903PMC
December 2013

ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer.

J Clin Invest 2013 Mar 15;123(3):1109-22. Epub 2013 Feb 15.

Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.

Fusion of the androgen receptor-regulated (AR-regulated) TMPRSS2 gene with ERG in prostate cancer (PCa) causes androgen-stimulated overexpression of ERG, an ETS transcription factor, but critical downstream effectors of ERG-mediating PCa development remain to be established. Expression of the SOX9 transcription factor correlated with TMPRSS2:ERG fusion in 3 independent PCa cohorts, and ERG-dependent expression of SOX9 was confirmed by RNAi in the fusion-positive VCaP cell line. SOX9 has been shown to mediate ductal morphogenesis in fetal prostate and maintain stem/progenitor cell pools in multiple adult tissues, and has also been linked to PCa and other cancers. SOX9 overexpression resulted in neoplasia in murine prostate and stimulated tumor invasion, similarly to ERG. Moreover, SOX9 depletion in VCaP cells markedly impaired invasion and growth in vitro and in vivo, establishing SOX9 as a critical downstream effector of ERG. Finally, we found that ERG regulated SOX9 indirectly by opening a cryptic AR-regulated enhancer in the SOX9 gene. Together, these results demonstrate that ERG redirects AR to a set of genes including SOX9 that are not normally androgen stimulated, and identify SOX9 as a critical downstream effector of ERG in TMPRSS2:ERG fusion-positive PCa.
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http://dx.doi.org/10.1172/JCI66666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582143PMC
March 2013

Cross-talk between HER2 and MED1 regulates tamoxifen resistance of human breast cancer cells.

Cancer Res 2012 Nov 10;72(21):5625-34. Epub 2012 Sep 10.

Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.

Despite the fact that most breast cancer patients have estrogen receptor (ER) α-positive tumors, up to 50% of the patients are or soon develop resistance to endocrine therapy. It is recognized that HER2 activation is one of the major mechanisms contributing to endocrine resistance. In this study, we report that the ER coactivator MED1 is a novel cross-talk point for the HER2 and ERα pathways. Tissue microarray analysis of human breast cancers revealed that MED1 expression positively correlates most strongly with HER2 status of the tumors. MED1 was highly phosphorylated, in a HER2-dependent manner, at the site known to be critical for its activation. Importantly, RNAi-mediated attenuation of MED1 sensitized HER2-overexpressing cells to tamoxifen treatment. MED1 and its phosphorylated form, but not the corepressors N-CoR and SMRT, were recruited to the ERα target gene promoter by tamoxifen in HER2-overexpressing cells. Significantly, MED1 attenuation or mutation of MED1 phosphorylation sites was sufficient to restore the promoter recruitment of N-CoR and SMRT. Notably, we found that MED1 is required for the expression of not only traditional E2-ERα target genes but also the newly described EGF-ERα target genes. Our results additionally indicated that MED1 is recruited to the HER2 gene and required for its expression. Taken together, these findings support a key role for MED1 in HER2-mediated tamoxifen resistance and suggest its potential usage as a therapeutic target to simultaneously block both ERα and HER2 pathways for the treatment of this type of endocrine resistant breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-1305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141533PMC
November 2012

Mapping mutations in prostate cancer exomes.

Asian J Androl 2012 Nov 30;14(6):801-2. Epub 2012 Jul 30.

Ohio State Biochemistry Graduate Program, The Ohio State University College of Medicine, Columbus, OH 43210, USA.

Comprehensive identification of driver mutations in prostate cancer can serve to enhance our understanding of the disease and expand the use of available treatment options. Two recent and complementary studies from Barbieri et al.1 and Grasso et al.2 have reported the results of exome sequencing analysis in large cohorts of primary, treatment-naïve and lethal castration-resistant prostate cancer (CRPC) cases, respectively. Together, these analyses revealed a number of novel genetic mutations representing uncharacterized drivers as well as combinations of mutations that may define important prostate cancer subtypes.
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http://dx.doi.org/10.1038/aja.2012.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720115PMC
November 2012

Integration of Hi-C and ChIP-seq data reveals distinct types of chromatin linkages.

Nucleic Acids Res 2012 Sep 6;40(16):7690-704. Epub 2012 Jun 6.

Department of Biomedical Informatics, 460 W 12th Avenue, 212 BRT, The Ohio State University, Columbus, OH 43210, USA.

We have analyzed publicly available K562 Hi-C data, which enable genome-wide unbiased capturing of chromatin interactions, using a Mixture Poisson Regression Model and a power-law decay background to define a highly specific set of interacting genomic regions. We integrated multiple ENCODE Consortium resources with the Hi-C data, using DNase-seq data and ChIP-seq data for 45 transcription factors and 9 histone modifications. We classified 12 different sets (clusters) of interacting loci that can be distinguished by their chromatin modifications and which can be categorized into two types of chromatin linkages. The different clusters of loci display very different relationships with transcription factor-binding sites. As expected, many of the transcription factors show binding patterns specific to clusters composed of interacting loci that encompass promoters or enhancers. However, cluster 9, which is distinguished by marks of open chromatin but not by active enhancer or promoter marks, was not bound by most transcription factors but was highly enriched for three transcription factors (GATA1, GATA2 and c-Jun) and three chromatin modifiers (BRG1, INI1 and SIRT6). To investigate the impact of chromatin organization on gene regulation, we performed ribonucleicacid-seq analyses before and after knockdown of GATA1 or GATA2. We found that knockdown of the GATA factors not only alters the expression of genes having a nearby bound GATA but also affects expression of genes in interacting loci. Our work, in combination with previous studies linking regulation by GATA factors with c-Jun and BRG1, provides genome-wide evidence that Hi-C data identify sets of biologically relevant interacting loci.
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http://dx.doi.org/10.1093/nar/gks501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439894PMC
September 2012

Integrated analysis identifies a class of androgen-responsive genes regulated by short combinatorial long-range mechanism facilitated by CTCF.

Nucleic Acids Res 2012 Jun 16;40(11):4754-64. Epub 2012 Feb 16.

Department of Statistics, The Ohio State University, Columbus, OH 43210, USA.

Recently, much attention has been given to elucidate how long-range gene regulation comes into play and how histone modifications and distal transcription factor binding contribute toward this mechanism. Androgen receptor (AR), a key regulator of prostate cancer, has been shown to regulate its target genes via distal enhancers, leading to the hypothesis of global long-range gene regulation. However, despite numerous flows of newly generated data, the precise mechanism with respect to AR-mediated long-range gene regulation is still largely unknown. In this study, we carried out an integrated analysis combining several types of high-throughput data, including genome-wide distribution data of H3K4 di-methylation (H3K4me2), CCCTC binding factor (CTCF), AR and FoxA1 cistrome data as well as androgen-regulated gene expression data. We found that a subset of androgen-responsive genes was significantly enriched near AR/H3K4me2 overlapping regions and FoxA1 binding sites within the same CTCF block. Importantly, genes in this class were enriched in cancer-related pathways and were downregulated in clinical metastatic versus localized prostate cancer. Our results suggest a relatively short combinatorial long-range regulation mechanism facilitated by CTCF blocking. Under such a mechanism, H3K4me2, AR and FoxA1 within the same CTCF block combinatorially regulate a subset of distally located androgen-responsive genes involved in prostate carcinogenesis.
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http://dx.doi.org/10.1093/nar/gks139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367180PMC
June 2012