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

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE180036 | GEO | 2025/06/16

REPOSITORIES: GEO

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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]

2025-06-16 | GSE180035 | GEO

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

2025-06-16 | GSE180034 | GEO

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

2025-06-16 | GSE213905 | GEO

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

| PRJNA1240300 | ENA

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-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]

| PRJNA746406 | ENA

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 CRISPRi Screen in Human iNeurons to Identify Novel Focal Cortical Dysplasia Genes.

Project description:Focal cortical dysplasia (FCD) is a common cause of focal epilepsy that typically results from brain mosaic mutations in the mTOR cell signaling pathway. To identify new FCD genes, we developed an in vitro CRISPRi screen in human neurons and used FACS enrichment based on the FCD biomarker, phosphorylated S6 ribosomal protein (pS6). Using whole-genome (110,000 gRNAs) and candidate (129 gRNAs) libraries, we discovered 12 new genes that significantly increase pS6 levels. Interestingly, positive hits were enriched for brain-specific genes, highlighting the effectiveness of using human iPSC-derived induced neurons (iNeurons) in our screen. We investigated the signaling pathways of six candidate genes: LRRC4, EIF3A, TSN, HIP1, PIK3R3, and URI1. All six genes increased phosphorylation of S6. However, only two genes, PIK3R3 and HIP1, caused hyperphosphorylation more proximally in the AKT/mTOR/S6 signaling pathway. Importantly, these two genes have recently been found independently to be mutated in resected brain tissue from FCD patients, supporting the predictive validity of our screen. Knocking down each of the other four genes (LRRC4, EIF3A, TSN, and URI1) in iNeurons caused them to become resistant to the loss of growth factor signaling; without growth factor stimulation, pS6 levels were comparable to growth factor stimulated controls. Our data markedly expand the set of genes that are likely to regulate mTOR pathway signaling in neurons and provide additional targets for identifying somatic gene variants that cause FCD.

| S-EPMC10760100 | biostudies-literature

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