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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 [ribosome profiling]

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 | GSE116082 | GEO

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

2019-07-31 | GSE116081 | 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 [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

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

Project description:Our study using prostate cancer tissues and cell lines observed that neuropilin-2 (NRP2) can translocate to the nucleus of advanced prostate cancer cells. NRP2 is present in the nuclear membrane and near to the nuclear pore. To understand the functions of nuclear NRP2 in prostate cancer, we have performed NRP2-specific chromatin immunoprecipitation DNA-sequencing (ChIP-seq) in prostate cancer cell. Our results showed NRP2 forms a complex with transcription factors and pore proteins, which helps the transcription factors to be recruited at the promoter regions of genes. The nature of the interaction between NRP2-transcription factors is dynamic and depends on various physiological and pathological conditions. The ChIP-seq was carried in duplicate using adenocarcinoma cell lines.

2022-06-03 | GSE205148 | GEO

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

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