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A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [RNA-seq]

ABSTRACT: We report that PRRX2 mediates enzalutamide resistance by activating the anti-apoptotic BCL2 and theE2F/RB1 cell cycle pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199538 | GEO | 2022/03/30

REPOSITORIES: GEO

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A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [ATAC-seq]

Project description:We report that PRRX2 mediates enzalutamide resistance by activating the anti-apoptotic BCL2 and theE2F/RB1 cell cycle pathways.

2022-03-30 | GSE199537 | GEO

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer

Project description:A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer

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A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer.

Project description:Androgen receptor (AR) pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance to therapy is common. Here, we used a CRISPR activation screen in metastatic castration-sensitive prostate cancer cells to identify genes that promote resistance to AR inhibitors. Activation of the TGFβ target gene paired-related homeobox2 (PRRX2) promoted enzalutamide resistance. PRRX2 expression was the highest in double-negative prostate cancer (DNPC), which lack AR signaling and neuroendocrine differentiation, and a PRRX2-related gene signature identified a subset of patients with DNPC with reduced overall survival. PRRX2-expressing cells showed alterations in the CDK4/6/Rb/E2F and BCL2 pathways. Accordingly, treatment with CDK4/6 and BCL2 inhibitors sensitized PRRX2-expressing, castration-resistant tumors to enzalutamide. Overall, PRRX2 was identified as a driver of enzalutamide resistance. The PRRX2 signature merits investigation as a biomarker of enzalutamide resistance in prostate cancer that could be reversed with CDK4/6 and BCL2 inhibitors.SignificancePRRX2 mediates enzalutamide resistance via activation of the E2F and BCL2 pathways, which can be targeted with CDK4/6 and BCL2 inhibitors to reverse resistance.

| S-EPMC9177667 | biostudies-literature

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [ATAC-seq]

Project description:A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [ATAC-seq]

| PRJNA820696 | ENA

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [RNA-seq]

Project description:A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer [RNA-seq]

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Expression data from prostate cancer cell lines C4-2B (enzalutamide sensitive) and C4-2B-MDVR (enzalutamide resistant) cells

Project description:Prostate cancer C4-2B cells were cultured in enzalutamide in a dose-escalation manner. After sixty passages cells were resistant to enzalutamide, with a specific sets of genes been deregulated. We performed global gene expression analysis by cDNA microarrays to identify genes responsible for enzalutamide resistance in C4-2B-MDVR cells. Enzalutamide resistant C4-2B-MDVR cells were selected from C4-2B cells during long time enzalutamide treatment. Genes responsible for enzalutamide resistance were identified using C4-2B vs. C4-2B-MDVR RNA extraction and hybridization on Affymetrix microarrays.

2015-04-09 | E-GEOD-64143 | biostudies-arrayexpress

Genome-wide CRISPR Knockout Screen in LNCaP Cells Treated with Enzalutamide

Project description:To categorize gene loss events in enzalutamide-treated LNCaP cells, a genome-wide CRISPR knockout (KO) screen was performed. We quantified sgRNA abundance between initial and final timepoints in DMSO and enzalutamide treated cell populations

2024-09-30 | GSE226977 | GEO

A genome-wide CRISPR activation screen identifies PRRX2 as a regulator of enzalutamide resistance in prostate cancer

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

2022-03-30 | GSE199539 | GEO

A genome-wide CRISPR screen identifies HuR as a regulator of apoptosis induced by dsRNA and viral infection

Project description:Cell death is an important host defense in response to viral infections. In this study,we performed an unbiased whole-genome CRISPR/Cas9 screen in A549 lung adenocarcinoma cells to identify potential regulators involved in cell death triggered dsRNA, a common byproduct of viral replication. Of several top candidate genes, we identified the RNA binding protein ELAV like protein 1 (ELAVL1) (ELAVL1, also called HuR) that encodes Hu antigen R (HuR). Depletion of HuR by gene editing led to less cell death induced by dsRNA. We further demonstrated that HuR regulated apoptosis, and the RNA recognition motif (RRM) 3 of HuR was essential for its proapoptotic function. HuR bound mRNA of anti-apoptotic gene BCL2. HuR depletion had no influence on BCL2 mRNA levels, but instead downregulated the BCL2 translation. Polysome fractionation studies showed that HuR retarded the BCL2 mRNA in the non-translating pool of polysomes. Moreover, protection from dsRNA-induced apoptosis by HuR depletion required the presence of BCL2, indicating that the proapoptotic function of HuR is executed by suppressing BCL2. Consistently, HuR regulated apoptosis induced by infection of encephalomyocarditis or Semliki Forest virus, two unrelated positive strand RNA viruses. Collectively, our work identified a suite of proteins that regulate dsRNA-induced cell death, and elucidated the mechanism by which HuR acts as a pro-apoptotic factor.

2021-01-28 | GSE165625 | GEO

FMNL2/SRC-mediated androgen receptor translocation into the nucleus promotes enzalutamide resistance of prostate cancer

Project description:Enzalutamide, a second-generation androgen receptor (AR) antagonist, has represented the association with improved overall survival in men with prostate cancer (PCa). However, PCa patients receiving enzalutamide will eventually develop resistance through various mechanisms without effective regimens. Here, we observed a higher level of formin-like 2 (FMNL2) in enzalutamide-resistant PCa cells. Functionally, FMNL2 knockdown partially re-sensitized enzalutamide-resistant PCa cells. Mechanistically, FMNL2 directly interacted with SRC kinase through FMNL2-FH1 and SRC-SH3 domain, which induced AR translocation from the cytoplasm to the nucleus, resulting in increased expression of the AR-targeted genes and leading to resistance to enzalutamide. Consistently, SRC inhibitor dasatinib rescued enzalutamide sensitivity and inhibited the proliferation of enzalutamide-resistant cancer cells. Taken together, our findings demonstrate a substantial role for FMNL2/SRC interaction in the regulation of AR translocation, suggesting that targeting FMNL2-mediated SRC activation might be a potential therapeutic strategy for enzalutamide-resistant PCa, and dasatinib could be an option.

2025-01-13 | PXD059539 | Pride

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