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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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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.

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

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A pathogenic Th17/CD38+ macrophage feedback loop drives inflammatory arthritis through TNFa

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An autoregulatory feedback loop converging on H2AK119ub1 drives synovial sarcoma [CUT&RUN]

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An autoregulatory feedback loop converging on H2AK119ub1 drives synovial sarcoma [CUT&RUN]

Project description:The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of mSWI/SNF complex, to polycomb repressive complex 1 (PRC1) target genes. Here we show that the SSX C-terminus, via its SSXRD domain, directs SS18-SSX chromatin binding independently of SS18. SSXRD specific targeting is mediated by interaction with H2AK119ub1 and histone MacroH2A with which the fusion overlaps genome wide. Variant Polycomb Repressive Complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and consequently is required for SS18-SSX occupancy. Importantly, SSX C-terminus not only depends on H2AK119ub1 for localization but also further promotes it and consequently, high H2AK119ub1 levels are acquired during synovial sarcoma development. These results reveal an SS18-SSX/PRC1 autoregulatory feedback-loop that enforces fusion binding and could play a role in a wide-range of cancers and physiological settings where SSX proteins are overexpressed.

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