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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

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

ORGANISM(S): Mus musculus

PROVIDER: GSE116083 | GEO | 2019/07/31

REPOSITORIES: GEO

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer.

Project description:The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.

| S-EPMC6746573 | biostudies-literature

The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [RNA-seq]

Project description:The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has had the unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular, non-neuroendocrine androgen receptor-low castration resistant prostate cancer (AR low CRPC) is increasing in occurrence amongst patients and is uniformly fatal. The mechanisms that promote this phenotype remain poorly understood. Through molecular studies of murine and human models of AR low CRPC, we have identified a new functional interface between the androgen receptor and the translation initiation complex inhibitor 4EBP1. AR directly regulates 4EBP1 expression which translationally represses eIF4F complex formation and a pro-proliferation program. In the context of AR low prostate cancer, de-repression of translation initiation drives the aberrant expression of the pro-proliferation regulon which fuels uncontrolled cell growth. Genetic and pharmacologic inhibition of the downstream eIF4F translation initiation complex reverses the proliferation phenotype in vitro and in vivo. These findings reveal a new previously unrecognized druggable nexus which functionally link the processes of mRNA transcription and translation initiation in a rapidly emerging class of advanced lethal prostate cancer

2019-07-31 | GSE116081 | GEO

The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [ribosome profiling]

2019-07-31 | GSE116082 | GEO

The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

Project description:The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

| PRJNA476967 | ENA

The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [ribosome profiling]

Project description:The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [ribosome profiling]

| PRJNA476979 | ENA

The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [RNA-seq]

Project description:The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [RNA-seq]

| PRJNA476980 | ENA

Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-03 | GSE205150 | GEO

Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer.

Project description:Aberrant transcriptional activity of androgen receptor (AR) is one of the dominant mechanisms for developing of castration-resistant prostate cancer (CRPC). Analyzing AR-transcriptional complex related to CRPC is therefore important towards understanding the mechanism of therapy resistance. While studying its mechanism, we observed that a transmembrane protein called neuropilin-2 (NRP2) plays a contributory role in forming a novel AR-transcriptional complex containing nuclear pore proteins. Using immunogold electron microscopy, high-resolution confocal microscopy, chromatin immunoprecipitation, proteomics, and other biochemical techniques, we delineated the molecular mechanism of how a specific splice variant of NRP2 becomes sumoylated upon ligand stimulation and translocates to the inner nuclear membrane. This splice variant of NRP2 then stabilizes the complex between AR and nuclear pore proteins to promote CRPC specific gene expression. Both full-length and splice variants of AR have been identified in this specific transcriptional complex. In vitro cell line-based assays indicated that depletion of NRP2 not only destabilizes the AR-nuclear pore protein interaction but also inhibits the transcriptional activities of AR. Using an in vivo bone metastasis model, we showed that the inhibition of NRP2 led to the sensitization of CRPC cells toward established anti-AR therapies such as enzalutamide. Overall, our finding emphasize the importance of combinatorial inhibition of NRP2 and AR as an effective therapeutic strategy against treatment refractory prostate cancer.

| S-EPMC9979947 | biostudies-literature

Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer.

Project description:The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.

| S-EPMC2726827 | biostudies-literature

Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer [RNA-seq]

Project description:Gene expression was first compared between control and NRP2 depletd condition in prostate adenocarcinoma cell line LNCaP C4-2B . In the next set, we compared the gene expression between control and AR deplted state in LNCaP C4-2B cells.

2022-06-03 | GSE205149 | GEO

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