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Genome-wide occupation of AR, FOXA1, and H3K27AC in LNCaP cells treated with selective PARP2 inhibitor UPF-1069

ABSTRACT: Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated transcription provides new opportunities for therapeutic intervention. We have previously discovered that a genetic variant in one of the DNA repair genes, PARP2, is associated with aggressive PCa. Here, we show that a high expression level of PARP2 in PCa tumors is associated with high Gleason scores and biochemical recurrence using The Cancer Genome Atlas (TCGA) dataset. Functional studies reveal that PARP2 enhances AR-mediated gene expression through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to the enhancer regions genome-wide in PCa cells. Selective targeting of PARP2, but not PARP1, by genetic or pharmacological means blocks interaction between PARP2 and FOXA1, which in turn attenuates AR-mediated transcription and inhibits AR-positive PCa growth. SIGNIFICANCE: Current anti-androgens act through blocking ligand binding or inhibiting androgen synthesis. Selective targeting of PARP2 may provide a novel therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA repair defect status and, more importantly, when direct AR-targeted therapies fail.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114274 | GEO | 2019/06/24

REPOSITORIES: GEO

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Gene expression profilings for prostate cancer cells after inhibition of PARP1 or PARP2 using pharmaceutical or siRNA-based approaches

Project description:Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated transcription provides new opportunities for therapeutic intervention. We have previously discovered that a genetic variant in one of the DNA repair genes, PARP2, is associated with aggressive PCa. Here, we show that a high expression level of PARP2 in PCa tumors is associated with high Gleason scores and biochemical recurrence using The Cancer Genome Atlas (TCGA) dataset. Functional studies reveal that PARP2 enhances AR-mediated gene expression through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to the enhancer regions genome-wide in PCa cells. Selective targeting of PARP2, but not PARP1, by genetic or pharmacological means blocks interaction between PARP2 and FOXA1, which in turn attenuates AR-mediated transcription and inhibits AR-positive PCa growth. SIGNIFICANCE: Current anti-androgens act through blocking ligand binding or inhibiting androgen synthesis. Selective targeting of PARP2 may provide a novel therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA repair defect status and, more importantly, when direct AR-targeted therapies fail.

2019-06-24 | GSE114273 | GEO

Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells [RNAseq_mTOR]

Project description:mTOR is a serine/threonine kinase that controls prostate cancer (PCa) cell growth in part by regulating gene programs associated with metabolic and cell proliferation pathways. mTOR- mediated control of gene expression can be achieved via phosphorylation of transcription factors, leading to changes in their cellular localization and activities. mTOR also directly associates with chromatin in complex with transcriptional regulators, including the androgen receptor (AR). Nuclear mTOR (nmTOR) has been previously shown to act as a transcriptional integrator of the androgen signaling pathway in association with the chromatin remodeling machinery, AR, and FOXA1. However, the contribution of cytoplasmic mTOR (cmTOR) and nmTOR and the role played by FOXA1 in this process remains to be explored. Herein, we engineered cells expressing mTOR tagged with nuclear localization and export signals dictating mTOR localization. Transcriptome profiling in AR-positive PCa cells revealed that nmTOR generally downregulates a subset of the androgen response pathway independently of its kinase activity, while cmTOR upregulates a cell cycle-related gene signature in a kinase-dependent manner. Biochemical and genome-wide transcriptomic analyses demonstrate that nmTOR functionally interacts with AR and FOXA1. Ablation of FOXA1 reprograms the nmTOR cistrome and transcriptome of androgen responsive PCa cells. This works highlights a transcriptional regulatory pathway in which direct interactions between nmTOR, AR and FOXA1 dictate a combinatorial role for these factors in the control of specific gene programs in PCa cells.

2023-07-19 | GSE225205 | GEO

Canonical and nuclear mTOR specify distinct transcriptional programs in androgen-dependent prostate cancer cells [ChIP-Seq]

2023-10-11 | GSE225196 | GEO

Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence

Project description:In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various stages of the disease. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. In addition, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin binding sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian rhythm core component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL suppression decreased cell growth in vitro. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.

2022-10-14 | PXD032041 | Pride

Single-Cell Analysis Reveals Androgen Receptor Regulates ER-to-Golgi Trafficking with CREB3L2 To Drive Prostate Cancer Progression

Project description:Androgen receptor (AR) plays an essential role in normal prostate development and prostate cancer (PCa) progression. To understand the role of AR at the single-cell level, we performed single-cell transcriptome analysis on PCa cells stimulated with androgen and antiandrogen to reconstruct the dynamic and direct AR transcriptional network. Our work reveals that androgen stimulates the ER and Golgi stress response , promoting secreting protein trafficking, and inhibiting cell apoptosis. Moreover, we identify an ER-to-Golgi protein vesicle-mediated transport gene signature essential for maximal androgen-mediated ER-Golgi trafficking, cell proliferation, and association with PCa prognosis and progression. Notably, we show that AR collaborates with CREB3L2, XXX, to coordinately promote ER-Golgi trafficking of Golgi enzyme Mannosidase II and PCa cell survival. Finally, we show the inhibition of the ER-Golgi transport process with Brefeldin A leads to tumor regression. Our study collectively reveals the heterogeneity of PCa cell transcriptional response to androgen stimulation, demonstrates a functional role for increased ER-Golgi trafficking process, and provides a mechanism for how the process is augmented in PCa as well as the potential of targeting may provide novel treatment strategies.

2021-10-10 | GSE165562 | GEO

The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity cancer.

Project description:The androgen receptor (AR) plays a central role in the development of castration resistant prostate cancer (CRPC). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination dependent degradation, thereby promoting the expression of ~13% of AR target genes. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under androgen-deprivation conditions in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity.

2013-02-15 | GSE44319 | GEO

Endogenous androgen receptor proteomic profiling reveals genomic subcomplex involved in prostate tumorigenesis

Project description:Androgen receptor (AR) is a key player in prostate cancer development and progression. Here we applied immunoprecipitation mass spectrometry of endogenous AR in LNCaP cells to identify components of the AR transcriptional complex. In total, 66 known and novel AR interactors were identified in the presence of synthetic androgen, most of which were critical for AR-driven prostate cancer cell proliferation. A subset of AR interactors required for LNCaP proliferation were profiled using chromatin immunoprecipitation assays followed by sequencing, identifying distinct genomic subcomplexes of AR interaction partners. Interestingly, three major subgroups of genomic subcomplexes were identified, where selective gain of function for AR genomic action in tumorigenesis was found, dictated by FOXA1 and HOXB13. In summary, by combining proteomic and genomic approaches we reveal subclasses of AR transcriptional complexes, differentiating normal AR behavior from the oncogenic state. In this process, the expression of AR interactors has key roles by reprogramming the AR cistrome and interactome in a genomic location-specific manner.

2017-10-27 | PXD008056 | Pride

Amplitude modulation of androgen signaling by c-MYC [ChIP-Seq]

Project description:Androgen-stimulated growth of the molecular apocrine breast cancer is mediated by an androgen receptor (AR)-regulated transcriptional program. Through profiling the genomic licalizations of AR and its co-regulators FOXA1 and TCF7L2 in MDA-MB-453 breast cancer cells, we revealed the molecular details of the AR-centered regulatory network. We further identified that c-MYC is a key downstream target co-regulated by AR, FOXA1 and TCF7L2, and reinforces the transctiopnal activation of androgen-responsive genes in this subtype of breast cancers. AR and FOXA1 ChIP-seq were performed in MDA-MB-453 breast cancer cells with treatment of 5a-dihydrotestosterone (DHT) for 16 h. TCF7L2 ChIP-seq was performed in MDA-MB-453 cells treated with vehicle or DHT for 16 h, respectively. MYC ChIP-seq was performed in MDA-MB-453 cells following 6 h DHT stimulation.

2013-03-16 | E-GEOD-45201 | biostudies-arrayexpress

RUNX2 selectively attenuates or augments androgen-driven transcription in prostate cancer

Project description:Prostate carcinogenesis is associated with changes in androgen signaling from driving cellular differentiation to promoting oncogenic behaviors. RUNX2 binds the androgen receptor (AR), and ectopic expression of RUNX2 is linked to prostate cancer (PCa) progression. We therefore investigated genome-wide the influence of RUNX2 on androgen-induced gene expression and AR DNA binding in PCa cells. The predominant function of RUNX2 is to inhibit the androgen response, attributable in part to dissociation of AR from target genes such as the tumor suppressor NKX3-1. At a minority of AR target genes, however, AR activity persists in the presence of RUNX2. Some of these genes are co-operatively stimulated by androgen and RUNX2 signaling and are characterized by the presence of putative enhancers co-occupied by AR and RUNX2. Genes synergistically stimulated by AR and RUNX2 include the invasion-promoting transcription factor SNAI2. Indeed, co-activation of AR and RUNX2, but neither alone, stimulated PCa cell invasiveness, which was abolished by SNAI2 silencing. Accordingly, PCa biopsies most strongly stained for SNAI2 exhibit high nuclear expression of both RUNX2 and AR. The RUNX2-mediated locus-dependent modulation of AR activity in PCa opens a research avenue that may guide the development of novel diagnostic and therapeutic approaches to patient management. total RNA from C4-2B/Rx2dox cells was extracted in biological triplicates from four different conditions. Ethanol vehicle control, dox to induce RUNX2 expression, DHT to activate androgen receptor and DHT+dox combined.

2014-03-20 | E-GEOD-52627 | biostudies-arrayexpress

The role of AR-associated factors in androgen signaling

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2014-10-21 | E-GEOD-58309 | biostudies-arrayexpress

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