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A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

ABSTRACT: A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

PROVIDER: PRJNA638813 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11994638.fastq.gz	Fastqsanger.gz
	SRR11994639.fastq.gz	Fastqsanger.gz
	SRR11994640.fastq.gz	Fastqsanger.gz
	SRR11994641.fastq.gz	Fastqsanger.gz
	SRR11994642.fastq.gz	Fastqsanger.gz

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Similar Datasets

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

Project description:Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an AR-regulated gene that is upregulated in prostate cancer. Knockdown of 6PGD impairs growth and elicits death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using 2 specific inhibitors, physcion and S3. Both compounds exhibited substantial anti-cancer activity in multiple models of prostate cancer, including aggressive models of castration-resistant disease that are resistant to contemporary therapy. Mechanistically, 6PGD inhibits AMPK signalling, resulting in increased activity of the anabolic pathways regulated by ACC1 and mTOR. Importantly, the ability of S3 to inhibit prostate cancer growth was recapitulated in prospectively collected tumours using a patient-derived explant (PDE) system. Interestingly, inhibition of 6PGD decreases the expression and activity of AR in both cell lines and PDEs, revealing a novel positive feedback loop between these factors. Supporting the biological relevance of this feedback loop, co-targeting of AR and 6PGD was more effective than targeting either factor alone. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

2020-10-01 | GSE152254 | GEO

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth.

Project description:Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

| S-EPMC8416027 | biostudies-literature

Polycomb-mediated deactivation of AR-feedback loop leads to castration-resistant prostate cancer [gene expression]

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

Polycomb-mediated deactivation of AR-feedback loop leads to castration-resistant prostate cancer [ChIP-seq]

2017-02-19 | GSE79357 | GEO

A runaway PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma (ChIP-seq)

Project description:PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma

2018-12-28 | GSE124430 | GEO

A runaway PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma (RNA-Seq)

Project description:PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma

2018-12-28 | GSE124429 | GEO

Polycomb-Mediated Disruption of an Androgen Receptor Feedback Loop Drives Castration-Resistant Prostate Cancer.

Project description:The lethal phenotype of castration-resistant prostate cancer (CRPC) is generally caused by augmented signaling from the androgen receptor (AR). Here, we report that the AR-repressed gene CCN3/NOV inhibits AR signaling and acts in a negative feedback loop to block AR function. Mechanistically, a cytoplasmic form of CCN3 interacted with the AR N-terminal domain to sequester AR in the cytoplasm of prostate cancer cells, thereby reducing AR transcriptional activity and inhibiting cell growth. However, constitutive repression of CCN3 by the Polycomb group protein EZH2 disrupted this negative feedback loop in both CRPC and enzalutamide-resistant prostate cancer cells. Notably, restoring CCN3 was sufficient to effectively reduce CPRC cell proliferation in vitro and to abolish xenograft tumor growth in vivo Taken together, our findings establish CCN3 as a pivotal regulator of AR signaling and prostate cancer progression and suggest a functional intersection between Polycomb and AR signaling in CRPC. Cancer Res; 77(2); 412-22. ©2016 AACR.

| S-EPMC5243151 | biostudies-literature

A Positive Feedback Loop Between TGFβ and Androgen Receptors Supports Triple-Negative Breast Cancer Anoikis Resistance

Project description:A Positive Feedback Loop Between TGFβ and Androgen Receptors Supports Triple-Negative Breast Cancer Anoikis Resistance

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RSK1-driven TRIM28-E2F1 feedback loop promotes castration-resistant prostate cancer progression

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

A runaway PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma (ChIP-seq)

Project description:A runaway PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma (ChIP-seq)

| PRJNA512004 | ENA