Grainyhead-like 2 is essential for androgen receptor expression and activity in prostate cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA318923 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3379520.fastq.gz | Fastqsanger.gz | |||
| SRR3379511.fastq.gz | Fastqsanger.gz | |||
| SRR3379521.fastq.gz | Fastqsanger.gz | |||
| SRR3379512.fastq.gz | Fastqsanger.gz | |||
| SRR3379522.fastq.gz | Fastqsanger.gz |
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Project description:The mainstay treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT), which inhibits androgen biosynthesis and/or binding of ligand to the androgen receptor (AR). Most men respond to ADT, but all subsequently develop resistance and progression to incurable and lethal castration-resistant prostate cancer (CRPC). CRPC generally remains driven by the AR: therefore, the development of novel AR-targeted therapies, as well as elucidating therapy-driven changes to the AR signalling axis that mediate resistance, remain priorities for the field. Using a novel and powerful proteomic technique, rapid immunoprecipitation of endogenous proteins (RIME), we have identified a new AR binding protein, the transcription factor Grainyhead-like 2 (GRHL2), and shown that it plays an essential, multifaceted role in signalling by the canonical AR and by constitutively active truncated AR variants (ARVs). GRHL2 is necessary for the maintenance of AR/ARV expression in multiple prostate cancer model systems, co-localises with AR at specific sites on chromatin to enhance the androgen-regulated transcriptional program, and is required for optimal prostate cancer growth. Interestingly, we found that GRHL2 is itself an AR/ARV-regulated gene, creating a positive feed-forward loop between the two factors. The GRHL2 gene is frequently amplified and upregulated in CRPC, thereby potentially enabling further amplification AR signalling in the drug-resistant setting. In summary, this study has identified a critical new AR coregulator and potential therapeutic target in prostate cancer.
2017-04-01 | GSE80450 | GEO
Project description:The mainstay treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT), which inhibits androgen biosynthesis and/or binding of ligand to the androgen receptor (AR). Most men respond to ADT, but all subsequently develop resistance and progression to incurable and lethal castration-resistant prostate cancer (CRPC). CRPC generally remains driven by the AR: therefore, the development of novel AR-targeted therapies, as well as elucidating therapy-driven changes to the AR signalling axis that mediate resistance, remain priorities for the field. Using a novel and powerful proteomic technique, rapid immunoprecipitation of endogenous proteins (RIME), we have identified a new AR binding protein, the transcription factor Grainyhead-like 2 (GRHL2), and shown that it plays an essential, multifaceted role in signalling by the canonical AR and by constitutively active truncated AR variants (ARVs). GRHL2 is necessary for the maintenance of AR/ARV expression in multiple prostate cancer model systems, co-localises with AR at specific sites on chromatin to enhance the androgen-regulated transcriptional program, and is required for optimal prostate cancer growth. Interestingly, we found that GRHL2 is itself an AR/ARV-regulated gene, creating a positive feed-forward loop between the two factors. The GRHL2 gene is frequently amplified and upregulated in CRPC, thereby potentially enabling further amplification AR signalling in the drug-resistant setting. In summary, this study has identified a critical new AR coregulator and potential therapeutic target in prostate cancer.
2017-04-01 | GSE80256 | GEO
Project description:To investigate the mechanisms of drug resistance and castration resistance in prostate cancer, we performed proteomic sequencing on androgen-dependent prostate cancer cells (LNCaP) and androgen-independent cells (AI) treated with enzalutamide.
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Project description:Androgen receptor (AR) is a master transcription factor that drives prostate cancer (PCa) development and progression. Alterations in the expression or activity of AR coregulators significantly impact the disease's outcome. To identify all the essential components of the AR coregulator complex, we utilized a proteomic approach called rapid immunoprecipitation of endogenous proteins (RIME) to systematically identify all coregulator proteins of the AR interactome in PCa cells.
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Project description:Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies high AR activity score as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation
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Project description:Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies high AR activity score as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation
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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.
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Project description:This SuperSeries is composed of the following subset Series: GSE30622: Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer [Expression Array] GSE30623: Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer [ChIP_seq, DHS_seq] Refer to individual Series
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Project description:The aberrant expression of androgen receptor (AR)-dependent transcriptional programs is a defining pathology of the development and progression of prostate cancers. Transcriptional cofactors that bind AR are critical determinants of prostate tumorigenesis. To gain a deeper understanding of the proteins linked to AR-dependent gene transcription, we performed a DNAaffinity chromatography-based proteomic screen designed to identify proteins involved in ARmediated gene transcription in prostate tumor cells.
2015-09-03 | PXD002596 | Pride
Project description:Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies high AR activity score as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation
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