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Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR

ABSTRACT: Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR

PROVIDER: PRJNA1240300 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32810042_1.fastq.gz	Fastqsanger.gz
	SRR32810042_2.fastq.gz	Fastqsanger.gz
	SRR32810043_1.fastq.gz	Fastqsanger.gz
	SRR32810043_2.fastq.gz	Fastqsanger.gz
	SRR32810044_1.fastq.gz	Fastqsanger.gz

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Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR

Project description:Comprehensively understanding the gene regulatory network that modulates the biology of the Androgen Receptor (AR) oncogene is a central goal of prostate cancer research. To study regulators of AR, we knock-in a split neon green fluorescent protein onto the AR in prostate cancer cells creating an endogenous AR reporter cell line. Using our endogenous AR reporter, we performed a genome-scale fluorescence-activated cell sorting based CRISPRi screen to comprehensively identify genes that modulate AR protein levels. We identify and validate known AR protein regulators including HOXB13, GATA2, GRHL2 as well as unexpected top hits including PTGES3, SAE1 and CSNK2A1. Loss of PTGES3 in multiple models of ARSI-resistant Pca resulted in loss of AR protein and thus AR’s oncogenic activity. Mechanistically, we demonstrate a novel nuclear co-factor function of PTGES3 facilitating AR-mediated transcription aside from its canonical co-chaperone function regulating AR protein levels. Lastly using a disulfide tethering chemical screen, we developed a PTGES3 inhibitor demonstrating PTGES3 is a therapeutically tractable target for the treatment of AR-addicted mCRPC.

2025-06-16 | GSE292612 | GEO

Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [mRNA-seq]

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Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [ATAC-seq]

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Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [mRNA-seq_181-40]

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Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR

Project description:Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR

| PRJNA746320 | ENA

Genome-scale CRISPR screens identify PTGES3 as a direct modulator of AR function in advanced prostate cancer

Project description:The androgen receptor (AR) is a critical driver of prostate cancer (PCa). To study regulators of AR protein levels and oncogenic activity, we created the first live cell quantitative endogenous AR fluorescent reporters. Leveraging this novel AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators including HOXB13 and GATA2 and also unexpected top hits including PTGES3, a poorly characterized gene in PCa. PTGES3 repression resulted in loss of AR protein, cell cycle arrest, and cell death in AR-driven PCa models. PTGES3 is not a commonly essential gene, and our data nominate it as a prime PCa drug target. Clinically, analysis of PCa data demonstrate that PTGES3 expression is associated with AR directed therapy resistance. Mechanistically, we show PTGES3 binds directly to AR, forms a protein complex with AR in the nucleus, regulates AR protein stability in vitro and in vivo and modulates AR function in the nucleus at AR target genes. Lastly using a disulfide tethering fragment screen, we developed a PTGES3 covalent inhibitor that blocks the PTGES3/AR interaction and represses AR signaling in PCa cells, suggesting PTGES3 inhibitors may be a next generation AR-targeting therapeutic strategy that can overcome known mechanisms of resistance to existing AR-directed therapies in PCa.

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Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [ATAC-seq]

Project description:Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [ATAC-seq]

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Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [mRNA-seq]

Project description:Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [mRNA-seq]

| PRJNA746407 | ENA

Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [mRNA-seq_181-40]

Project description:Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR [mRNA-seq_181-40]

| PRJNA882921 | ENA

Genome-wide flow sorting CRISPRi screen identify PTGES3 as a novel therapeutic target of AR

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