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

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE205150 | GEO | 2022/06/03

REPOSITORIES: GEO

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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

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

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

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

| PRJNA844001 | ENA

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

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

| PRJNA844003 | ENA

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

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

| PRJNA844009 | ENA

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

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

2019-07-31 | GSE116083 | GEO

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

ZBTB7A Mediates the Transcriptional Repression Activity of the Androgen Receptor in Prostate Cancer.

Project description:Loss of expression of context-specific tumor suppressors is a critical event that facilitates the development of prostate cancer. Zinc finger and BTB domain containing transcriptional repressors, such as ZBTB7A and ZBTB16, have been recently identified as tumor suppressors that play important roles in preventing prostate cancer progression. In this study, we used combined ChIP-seq and RNA-seq analyses of prostate cancer cells to identify direct ZBTB7A-repressed genes, which are enriched for transcriptional targets of E2F, and identified that the androgen receptor (AR) played a critical role in the transcriptional suppression of these E2F targets. AR recruitment of the retinoblastoma protein (Rb) was required to strengthen the E2F-Rb transcriptional repression complex. In addition, ZBTB7A was rapidly recruited to the E2F-Rb binding sites by AR and negatively regulated the transcriptional activity of E2F1 on DNA replication genes. Finally, ZBTB7A suppressed the growth of castration-resistant prostate cancer (CRPC) in vitro and in vivo, and overexpression of ZBTB7A acted in synergy with high-dose testosterone treatment to effectively prevent the recurrence of CRPC. Overall, this study provides novel molecular insights of the role of ZBTB7A in CRPC cells and demonstrates globally its critical role in mediating the transcriptional repression activity of AR. SIGNIFICANCE: ZBTB7A is recruited to the E2F-Rb binding sites by AR and negatively regulates the transcriptional activity of E2F1 on DNA replication genes.

| S-EPMC6801099 | biostudies-literature

FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer.

Project description:Retention of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the requirement for the development of more effective AR targeting therapies. A key mechanism of resistance to anti-androgens is through expression of constitutively active AR variants (AR-Vs) that are refractory to next-generation therapies, including Enzalutamide and Abiraterone. By maintaining an androgenic gene signature, AR-Vs drive tumour survival and progression in castrate conditions. Critically, however, our understanding of the mechanics of AR-V-driven transcription is limited, particularly with respect to dependency on pioneer factor function. Here we show that depletion of FOXA1 in the CWR22Rv1 CRPC cell line abrogates the oncogenic potential of AR-Vs. Gene expression profiling reveals that approximately 41% of the AR-V transcriptome requires FOXA1 and that depletion of FOXA1 attenuates AR-V binding at a sub-set of analysed co-regulated genes. Interestingly, AR-V levels are elevated in cells depleted of FOXA1 as a consequence of attenuated negative feedback on the AR gene, but is insufficient to maintain cell growth as evidenced by marked anti-proliferative effects in FOXA1 knockdown cells. In all, our data suggests that AR-Vs are dependent on FOXA1 for sustaining a pro-proliferative gene signature and agents targeting FOXA1 may represent novel therapeutic options for CRPC patients.

| S-EPMC4745762 | biostudies-literature

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