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

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer death worldwide. Emerging evidence suggests that the androgen receptor (AR) is involved in ESCC tumorigenesis. However, how AR exerts its genomic functions in ESCC remains unknown. Here, by defining AR cistromes and analyzing androgen-regulated transcriptomes, we find that AR downregulates the majority of its target genes in ESCC cells. We further find that the pioneer factor GATA3 governs AR-repressed transcription by recruiting SMRT/HDAC3 co-repressors to target gene loci. Importantly, genetic inhibition of GATA3 or pharmacological inhibition of AR/HDAC3 relieves AR-mediated gene repression, leading to ESCC cell growth inhibition in vitro and in vivo. Our findings reveal molecular mechanisms underlying the oncogenomic function of AR in ESCC and identify the GATA3-directed AR transcriptional repression program as a therapeutic target for ESCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142556 | GEO | 2020/10/21

REPOSITORIES: GEO

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The¬¬¬ androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer

Project description:Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employed an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.

2024-01-30 | PXD047997 | Pride

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

2023-10-11 | MTBLS8034 | MetaboLights

Transcription profiling of human LNCaP prostate cancer cells to investigate the effect of HDAC inhibitors on expression of androgen induced genes

Project description:Elevated levels of androgen receptor (AR) in prostate cancer confer resistance to current antiandrogens and play a causal role in disease progression due to persistent target gene activation. Through pharmacologic and genetic approaches, we show that half of all direct AR target genes, including TMPRSS2, the primary driver of ETS fusion transcripts in 70 percent of human prostate cancers, require histone deacetylase (HDAC) activity for transcriptional activation by AR. Surprisingly, the HDAC3-NCoR complex, which typically functions to repress gene expression by nuclear receptors, is required for AR target gene activation. Prostate cancer cells treated with HDAC inhibitors have reduced AR protein levels, but we show that the mechanism of blockade of AR activity is through failure to assemble a coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in hormone refractory prostate cancer models and therefore merit clinical investigation in this setting. HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition. Experiment Overall Design: LNCaP prostate cancer cells were grown in charcoal stripped, androgen deplete medium. They were then stimulated with or without 1nM R1881 and with or without two doses of HDAC inhibitors TSA, SAHA, and LBH 589. Cyclohexamide was include to block new protein synthesis. Cells were harvested 16 hours after treatment.

2009-01-09 | E-GEOD-9000 | biostudies-arrayexpress

shRNA profiling of human luciferase (ctrl), HDAC1, HDAC2, and HDAC8 LnCAP cells were generated to examine the effect of individual HDAC knockdown on expression of androgen induced genes

Project description:Elevated levels of androgen receptor (AR) in prostate cancer confer resistance to current antiandrogens and play a causal role in disease progression due to persistent target gene activation. Through pharmacologic and genetic approaches, we show that half of all direct AR target genes, including TMPRSS2, the primary driver of ETS fusion transcripts in 70 percent of human prostate cancers, require histone deacetylase (HDAC) activity for transcriptional activation by AR. Surprisingly, the HDAC3-NCoR complex, which typically functions to repress gene expression by nuclear receptors, is required for AR target gene activation. Prostate cancer cells treated with HDAC inhibitors have reduced AR protein levels, but we show that the mechanism of blockade of AR activity is through failure to assemble a coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in hormone refractory prostate cancer models and therefore merit clinical investigation in this setting. HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition. Experiment Overall Design: Lentiviral shRNA mediated knockdown of Luciferase (ctrl), HDAC1, HDAC2, and HDAC8 LnCAP cells were generated. They were grown in charcoal stripped, androgen deplete medium. They were then stimulated with or without 1nM R1881. Cyclohexamide was include to block new protein synthesis. Cells were harvested 16 hours after treatment.

2009-01-14 | E-GEOD-12438 | biostudies-arrayexpress

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

Project description:The oncogenomic function of androgen receptor in esophageal squamous cell carcinoma is directed by GATA3

| PRJNA597367 | ENA

HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [RNA-Seq]

Project description:HOXB13 is a homeodomain transcription factor with prostate-specific expression. It is essential for normal prostate epithelium differentiation during development and functions as a key regulator of androgen-dependent cell growth in adult and cancerous prostate. Previous studies have demonstrated that HOXB13 is a pioneer factor of the androgen receptor (AR) and also a critical cofactor of AR variant v7 in castration-resistant prostate cancer (PCa). However, the intrinsic function of HOXB13 as a DNA-binding protein in an AR-independent context has not been elucidated. Here, our data reveal HOXB13, but not G84E mutant, recruits HDAC3 to specific genomic regions to catalyze histone de-acetylation and chromatin remodeling. We demonstrate a predominant function of HOXB13 in transcriptional repression of lipogenic genes requiring HDAC3.

2022-04-01 | GSE153585 | GEO

HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [ChIP-Seq]

2022-04-01 | GSE153583 | GEO

Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: kinetic analysis after DHT treatment

Project description:Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naïve advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq dataset and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity, and that this repressive function could be pathologically abrogated by AR variants in PCA.

2022-10-13 | PXD029520 | Pride

Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: BioID analysis

2022-10-14 | PXD029454 | Pride

AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-positive_PDX_GATA3_ChIP-seq]

Project description:GATA3 transcription factor is considered critical for luminal development and differentiation in normal and malignant mammary epithelial cells (MECs). The androgen receptor (AR) has also been associated with luminal gene expression profiles in breast cancer, independent of the estrogen receptor (ER), and has been shown to promote a basal to luminal phenotype transition in mouse MECs. To date, the potential interaction of GATA3 and AR in transcriptional regulation of lineage driver genes in breast cancer has never been investigated. Our unbiased proteomic analysis identified GATA3 as a novel AR interacting protein in a variety of breast cancer cell types regardless of ER expression. We showed that AR and GATA3 interact in the cytoplasm and nucleus of normal and malignant breast epithelia, an interaction increased by androgen treatment. Androgen stimulation of breast cancer cells also induced nuclear translocation of AR and GATA3 and resulted in enrichment of co-localized AR and GATA3 chromatin binding events. Using ER+ and/or ER- breast cancer cell lines and ER+ patient-derived xenograft (PDX) models of breast cancer, we identified a conserved subset of AR agonist-induced AR and GATA3 co-occupied cis-regulatory elements across all models. Knockdown experiments indicated that GATA3 acts as an AR co-regulator to upregulate transcription of known luminal-lineage genes (e.g. EHF, AQP3, and KDM4B) and downregulate basal-lineage genes (e.g. SMAD3 and ELK3). Also, we showed an induction in the chromatin accessibility at those subsets of common AR-GATA3 cis-regulatory elements, which drive the luminal lineage identity in breast cancer upon androgen stimulation. Collectively, AR-GATA3 interaction and function provide a mechanism underpinning epithelial breast cancer cells that are classified as having a luminal mature transcriptome independent of ER status, through regulating the expression of lineage-restricted markers.

2023-12-21 | GSE178254 | GEO

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