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MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE163146 | GEO | 2022/03/28

REPOSITORIES: GEO

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MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets.

Project description:c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

| S-EPMC9106722 | biostudies-literature

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Project description:c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Importantly, analyses of clinical specimens revealed that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed an increased RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

2022-03-28 | GSE163316 | GEO

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets [RNA-Seq]

Project description:c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Importantly, analyses of clinical specimens revealed that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed an increased RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

2022-03-28 | GSE163143 | GEO

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets [ChIP-Seq]

Project description:c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Importantly, analyses of clinical specimens revealed that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed an increased RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

2022-03-28 | GSE163145 | GEO

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Project description:MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

| PRJNA685750 | ENA

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets

Project description:MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets

| PRJNA685099 | ENA

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets [ChIP-Seq]

Project description:MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets [ChIP-Seq]

| PRJNA685105 | ENA

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets [RNA-Seq]

Project description:MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets at androgen receptor targets [RNA-Seq]

| PRJNA685104 | ENA

c-Myc regulates transcriptional pause release.

Project description:Recruitment of the RNA polymerase II (Pol II) transcription initiation apparatus to promoters by specific DNA-binding transcription factors is well recognized as a key regulatory step in gene expression. We report here that promoter-proximal pausing is a general feature of transcription by Pol II in mammalian cells and thus an additional step where regulation of gene expression occurs. This suggests that some transcription factors recruit the transcription apparatus to promoters, whereas others effect promoter-proximal pause release. Indeed, we find that the transcription factor c-Myc, a key regulator of cellular proliferation, plays a major role in Pol II pause release rather than Pol II recruitment at its target genes. We discuss the implications of these results for the role of c-Myc amplification in human cancer.

| S-EPMC2864022 | biostudies-literature

Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC.

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), termed 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 required high androgen receptor (AR) activity and were driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pretreatment AR activity predicted downregulation of MYC, improved 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 was overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and resensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.

| S-EPMC9711876 | biostudies-literature

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