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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213905 | 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.

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

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Resistance to AR Signaling Inhibition Does Not Necessitate Prostate Neuroendocrine Differentiation

Project description:Resistance to 2nd generation androgen receptor (AR) signaling inhibitors (ARSi) occurs in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients with the emergence of a neuroendocrine (NE) phenotype. This NE phenotype is typically accompanied by loss of AR expression coupled with mutations/deletions in PTEN, TP53, and/or RB1, in addition to overexpression of DNMTs, EZH2, and/or SOX2. A combination of cell and molecular biology analyses of 29 prostate cancer patient-derived xenografts (PDXs) recapitulating the full spectrum of proposed genetic alterations driving NE differentiation, in addition to CRISPR-Cas9 AR-knockout cells were utilized. These analyses document that: 1) ARSi-resistance in mCRPC cells that lack AR expression in the context of a TP53 mutation and PTEN deletion does not necessitate acquiring a NE phenotype, but alternatively can occur via emergence of an AR-/NE- double negative (DN) cancer; 2) NE cancers lack AR expression due to transcriptional silencing via promoter hypermethylation; and 3) in contrast, the lack of AR expression in DN cancers is not due to promoter hypermethylation-dependent silencing. Regardless of their cell of origin, the prevalence of both AR-/NE- DN and AR-/NE+ ARSi-resistant cancers is increasing clinically, highlighting the urgent need to develop therapies that target vulnerabilities beyond AR pathway inhibition.

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Role of androgen receptor splice variant 7 (AR-v7) in prostate cancer resistance to 2nd generation androgen receptor signaling inhibitors

Project description:Since its discovery, there has been one central issue of significant clinical relevance related to expression of the truncated androgen receptor splice variant-7 (AR-v7), which lacks the C-terminal ligand binding domain and thus acquires ligand-independent transcriptional activity in castration-resistant prostate cancer (CRPC). That question is whether AR-v7 is simply a marker of enhanced AR transcriptional activity characteristic of resistance to 2nd generation androgen receptor signaling inhibitors (ARSi) like Abiraterone and Enzalutamide, or whether it drives lethal resistance to ARSi. To address this question, the present study utilized 4 independently derived CRPC patient-derived xenografts in which the genetic and phenotypic changes could be followed before and after the development of ARSi resistance. This allowed evaluation of the correlation between acquired resistance to ARSi and changes in the expression levels of full length AR (AR-FL) vs. AR-v7 during this process. The combined results document that elevated expression of AR-FL alone is sufficient for Abiraterone- but not Enzalutamide-resistance. This is true even if AR-FL has a gain-of-function mutation. Furthermore, Enzalutamide-resistance is consistently correlated with the acquisition of AR-v7 expression. To directly test the requirement for AR-v7 expression in ARSi-refractory CRPC, CRISPR-Cas9 knockout of AR-FL and/or AR-v7 in LNCaP-95 cells was performed to evaluate in vitro and in vivo growth responses. These results document that AR-v7 drives Enzalutamide-resistance and focuses the critical need to develop therapeutic options to prevent and/or inhibit AR-v7 driven lethal progression of CRPC.

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Project description:Tumor recurrence and therapy resistance are generally accompanied by alterations in cellular metabolism. However, the mechanism by which metabolic conversion occurs and contributes to castration-resistant prostate cancer (CRPC) remains unclear. Here, we demonstrate that androgen receptor signaling inhibitors (ARSI)-induced mitochondrial oxidative phosphorylation (OXPHOS) is critical for CRPC development. Our findings indicate that prostate cancer cells exhibit increased mitochondrial OXPHOS following ARSI treatment; however, there is no significant change in glycolytic activity. Importantly, this metabolic conversion relies on increased glucose and glutamine utilization. Mechanistically, ARSI treatment induces oxidative stress, resulting in AMPK/PGC-1α-dependent metabolic conversion. High mitochondrial OXPHOS in turn renders prostate cancer cells resistant to ARSI. Pharmacological inhibition of mitochondrial OXPHOS shows promising treatment efficacy for CRPC and synergizes with ARSI to inhibit CRPC growth. Collectively, we demonstrate the metabolic plasticity of prostate cancer cells following ARSI treatment, identifying mitochondrial OXPHOS as a metabolic target for CRPC treatment.

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Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

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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

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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

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Acute BRCAness Induction and AR Signaling Blockage through CDK12/7/9 Degradation Enhances PARP Inhibitor Sensitivity in Prostate Cancer

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