Loss of Feedback Regulation between FAM3B and Androgen Receptor Driving Prostate Cancer Progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA864771 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20729653.fastq.gz | Fastqsanger.gz | |||
| SRR20729654.fastq.gz | Fastqsanger.gz | |||
| SRR20729655.fastq.gz | Fastqsanger.gz | |||
| SRR20729656.fastq.gz | Fastqsanger.gz | |||
| SRR20729657.fastq.gz | Fastqsanger.gz |
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Project description:TMPRSS2-ERG gene fusion is one of the most frequent genetic alterations in prostate cancer (PC). Through a systematical survey of the loss of interstitial genes and patient outcomes, we nominated FAM3B as the top-ranked interstitial genes whose loss is associated with a poor prognosis. Using cultured cells, patient- and cell-line-derived xenograft models in gonad-intact or castrated host, and genetically engineered mouse models with FAM3B overexpression, knockdown, or knockout, we defined a driver role of FAM3B loss in prostate cancer progression. By performing RNA-seq analysis in two pre-clinical models with ectopic FAM3B expression or FAM3B knockdown, we identified that the androgen response pathway was commonly modulated by FAM3B in these two models. Further validation studies showed that FAM3B inhibites AR activity.
2023-10-02 | GSE210202 | GEO
Project description:BackgroundAlthough the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression.MethodsWe conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome.ResultsThis analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling.ConclusionLoss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer.
| S-EPMC10919334 | biostudies-literature
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.
2024-11-26 | PXD058261 |
Project description:The androgen receptor (AR) plays a key role in progression to incurable androgen-ablation resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand binding domain (designated as AR3, AR4 and AR5) in hormone insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly upregulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells while specific knock-down of AR3 expression (without altering AR level) in hormone resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct yet essential role in ablation-independent growth through regulating a unique set of genes including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation-independence during PCA progression and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available anti-androgen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. Total RNA was extracted from CWR-R1 and 22Rv1 cells treated with shAR3-1, shARa and the scrambled shRNA control, respectively. Each of CWR-R1 and 22Rv1 cells treated with shAR3-1 was compared with the scrambled shRNA control. The same experiments were performed for the cells treated with shARa.
2009-03-16 | E-GEOD-13919 | biostudies-arrayexpress
Project description:Castration-resistant prostate cancer (CRPC) is a lethal disease, often characterized by aberrant androgen receptor (AR) activation independently of androgen. We have previously reported that AR can directly repress the expression of many target genes, one of which is NOV/CCN3. Here we show that NOV, primarily localized in the cytoplasm, physically interacts with AR at its Nterminus and sequesters AR and AR variants in the cytoplasm, thereby reducing AR chromatintargeting. This negative feedback loop, however, is disrupted in CRPC due to epigenetic silencing of NOV by the Polycomb group protein EZH2, rendering AR transcriptional activities and drug-resistant prostate cancer progression. Our findings thus suggest a working model wherein AR-repressed genes critically prevent CRPC through negative feedback loops inhibiting AR signaling.
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Project description:Castration-resistant prostate cancer (CRPC) is a lethal disease, often characterized by aberrant androgen receptor (AR) activation independently of androgen. We have previously reported that AR can directly repress the expression of many target genes, one of which is NOV/CCN3. Here we show that NOV, primarily localized in the cytoplasm, physically interacts with AR at its Nterminus and sequesters AR and AR variants in the cytoplasm, thereby reducing AR chromatintargeting. This negative feedback loop, however, is disrupted in CRPC due to epigenetic silencing of NOV by the Polycomb group protein EZH2, rendering AR transcriptional activities and drug-resistant prostate cancer progression. Our findings thus suggest a working model wherein AR-repressed genes critically prevent CRPC through negative feedback loops inhibiting AR signaling.
2017-02-19 | GSE79356 | GEO
Project description:Aberrant androgen receptor (AR)-mediated transcription is a critical driver in progression of human prostate cancer. It's known that different doses of androgens can elicit differential transcriptional and proliferative responses in prostate-tumor cells. Here, we set out to examine the androgenic regulation of glycoprotein expression in the membrane fraction of prostate-tumor cells that could serve as mediators or markers of androgen-induced proliferative responses observed in prostate-tumor cells. A bioanalytical workflow involving lectin-affinity chromatography and label-free quantitative mass spectrometry was used to identify androgen-sensitive glycomembrane protein expression associated with androgen-mediated proliferation. This study would facilitate the identification of surface membrane proteins involved in androgen-mediated proliferation and provide potential therapeutic targets in the detection treatment of proliferation prostate-tumors.
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Project description:Prostate carcinogenesis is associated with changes in androgen signaling from driving cellular differentiation to promoting oncogenic behaviors. RUNX2 binds the androgen receptor (AR), and ectopic expression of RUNX2 is linked to prostate cancer (PCa) progression. We therefore investigated genome-wide the influence of RUNX2 on androgen-induced gene expression and AR DNA binding in PCa cells. The predominant function of RUNX2 is to inhibit the androgen response, attributable in part to dissociation of AR from target genes such as the tumor suppressor NKX3-1. At a minority of AR target genes, however, AR activity persists in the presence of RUNX2. Some of these genes are co-operatively stimulated by androgen and RUNX2 signaling and are characterized by the presence of putative enhancers co-occupied by AR and RUNX2. Genes synergistically stimulated by AR and RUNX2 include the invasion-promoting transcription factor SNAI2. Indeed, co-activation of AR and RUNX2, but neither alone, stimulated PCa cell invasiveness, which was abolished by SNAI2 silencing. Accordingly, PCa biopsies most strongly stained for SNAI2 exhibit high nuclear expression of both RUNX2 and AR. The RUNX2-mediated locus-dependent modulation of AR activity in PCa opens a research avenue that may guide the development of novel diagnostic and therapeutic approaches to patient management. total RNA from C4-2B/Rx2dox cells was extracted in biological triplicates from four different conditions. Ethanol vehicle control, dox to induce RUNX2 expression, DHT to activate androgen receptor and DHT+dox combined.
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Project description:Castration-resistant prostate cancer (CRPC) marks the advanced and lethal stage of prostate cancer (PCa). TRIM28, also known as KAP1, is a transcriptional regulator recently shown to promote CRPC cell proliferation and xenograft tumor growth. Nonetheless, knowledge gaps persist regarding the mechanisms underlying TRIM28 upregulation in CRPC as well as the genomic targets regulated by TRIM28. Here, we report that TRIM28 is a novel E2F1-target in CRPC. Using an integrated genomic approach, we have demonstrated that TRIM28 forms a positive feedback loop to promote the transcription activation and genomic function of E2F1 independent of Rb status. Furthermore, we identified RSK1 as a kinase that directly phosphorylates TRIM28 at S473, and as such, RSK1 drives the TRIM28-E2F1 feedback loop. Accordingly, pS473-TRIM28 promotes CRPC progression, which is mitigated by RSK inhibition. In summary, our study reveals a critical role of the RSK1–TRIM28–E2F1 axis in CRPC progression, which may be exploited as a vulnerability in treating Rb-deficient CRPC.
2025-06-17 | GSE287229 | GEO
Project description:The androgen receptor (AR) plays a key role in progression to incurable androgen-ablation resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand binding domain (designated as AR3, AR4 and AR5) in hormone insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly upregulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells while specific knock-down of AR3 expression (without altering AR level) in hormone resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct yet essential role in ablation-independent growth through regulating a unique set of genes including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation-independence during PCA progression and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available anti-androgen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA.
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