CRISPR screens uncover protective effect of PSTK to targeted therapy induced ferroptosis in hepatocellular carcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA755280 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15477001_1.fastq.gz | Fastqsanger.gz | |||
| SRR15477001_2.fastq.gz | Fastqsanger.gz | |||
| SRR15477003_1.fastq.gz | Fastqsanger.gz | |||
| SRR15477003_2.fastq.gz | Fastqsanger.gz | |||
| SRR15477005_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 76 |
Similar Datasets
Project description:Hepatocellular carcinoma (HCC) is one of the most frequent malignancies with extremely poor prognosis. Clinical efficacies of existing targeted therapy strategies were not satisfied due to targeted therapy resistance. In this study, we performed a series of CRISPR/Cas9 screens to identify synthetic lethality genes to improve the clinical response of HCC. CRISPR loss-of-function genetic screens were performed to identify synthetic lethality genes of targeted therapies (Abemaciclib, Palbociclib, Sorafenib, Lenvatinib, Regorafenib and Erastin) in HCC cell lines. RNA-seq analysis were performed to clarify potential mechanism. We identified that inhibition of phosphoseryl-tRNA kinase (PSTK) sensitized HCC cells to targeted therapies. PSTK contributes to resistance of targeted therapy induced ferroptosis.
2022-03-23 | GSE182185 | GEO
Project description:BackgroundHepatocellular carcinoma (HCC) is among the most common forms of cancer and is associated with poor patient outcomes. The emergence of therapeutic resistance has hampered the efficacy of targeted treatments employed to treat HCC patients to date. In this study, we conducted a series of CRISPR/Cas9 screens to identify genes associated with synthetic lethality capable of improving HCC patient clinical responses.MethodsCRISPR-based loss-of-function genetic screens were used to target 18,053 protein-coding genes in HCC cells to identify chemotherapy-related synthetic lethal genes in these cells. Synergistic effects were analyzed through in vitro and in vivo analyses, while related mechanisms were explored through RNA-seq and metabolomics analyses. Potential inhibitors of identified genetic targets were selected through high-throughput virtual screening.ResultsThe inhibition of phosphoseryl-tRNA kinase (PSTK) was found to increase HCC cell sensitivity to chemotherapeutic treatment. PSTK was associated with the suppression of chemotherapy-induced ferroptosis in HCC cells, and the depletion of PSTK resulted in the inactivation of glutathione peroxidative 4 (GPX4) and the disruption of glutathione (GSH) metabolism owing to the inhibition of selenocysteine and cysteine synthesis, thus enhancing the induction of ferroptosis upon targeted chemotherapeutic treatment. Punicalin, an agent used to treat hepatitis B virus (HBV), was identified as a possible PSTK inhibitor that exhibited synergistic efficacy when applied together with Sorafenib to treat HCC in vitro and in vivo.ConclusionsThese results highlight a key role for PSTK as a mediator of resistance to targeted therapeutic treatment in HCC cells that functions by suppressing ferroptotic induction. PSTK inhibitors may thus represent ideal candidates for overcoming drug resistance in HCC.
| S-EPMC8725338 | biostudies-literature
Project description:Gamma interferon (IFN-γ) was reported to exhibit anti-tumor effects via inducing ferroptosis. Based on genome-wide CRISPR/Cas9 knockout screens, we discovered that cAMP response ele-ment binding protein (CREB) regulated transcription coactivator3 (CRTC3) protects tumor cells from drug induced ferroptosiis and is a significant resister of IFN-γ treatment in hepatocellular car-cinoma (HCC). Mechanically, CRTC3 knockout alters tumor cell lipid pattern and increases the abundance of polyunsaturated fatty acids (PUFAs), which facilitates lipid peroxidation and renders HCC cells susceptible to ferroptosis inducers. To scavenge accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells upregulate SLC7A11 expression to enhance the activity of glutamate-cystine antiporter (system xc-). As IFN-γ inhibiting system xc-, simultaneously treatment of IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. The sensitizing effect of CRTC3 depletion was further confirmed in typical ferroptosis inducers including RSL3, Erastin and Sorafeinib. Here, we reported a hitherto unexpected role of CRTC3 in regulating PUFAs metabolism and ferroptosis. Targeting the CRTC3 signaling in combination with ferroptosis inducers may represent a viable approach to treat cancer and overcome drug resistance in HCC.
2025-06-24 | GSE206906 | GEO
Project description:Gamma interferon (IFN-γ) was reported to exhibit anti-tumor effects via inducing ferroptosis. Based on genome-wide CRISPR/Cas9 knockout screens, we discovered that cAMP response ele-ment binding protein (CREB) regulated transcription coactivator3 (CRTC3) protects tumor cells from drug induced ferroptosiis and is a significant resister of IFN-γ treatment in hepatocellular car-cinoma (HCC). Mechanically, CRTC3 knockout alters tumor cell lipid pattern and increases the abundance of polyunsaturated fatty acids (PUFAs), which facilitates lipid peroxidation and renders HCC cells susceptible to ferroptosis inducers. To scavenge accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells upregulate SLC7A11 expression to enhance the activity of glutamate-cystine antiporter (system xc-). As IFN-γ inhibiting system xc-, simultaneously treatment of IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. The sensitizing effect of CRTC3 depletion was further confirmed in typical ferroptosis inducers including RSL3, Erastin and Sorafeinib. Here, we reported a hitherto unexpected role of CRTC3 in regulating PUFAs metabolism and ferroptosis. Targeting the CRTC3 signaling in combination with ferroptosis inducers may represent a viable approach to treat cancer and overcome drug resistance in HCC.
2025-06-24 | GSE206905 | GEO
Project description:CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma
| PRJNA852587 | ENA
Project description:CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma [CRISPR screen]
| PRJNA852589 | ENA
Project description:CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma [RNA-seq]
| PRJNA852588 | ENA
Project description:Ferroptosis is an iron-dependent cell death mechanism characterized by an accumulation of toxic lipid peroxides and membrane rupture. The glutathione dependent enzyme, GPX4 (glutathione peroxidase 4), prevents ferroptosis by reducing these lipid peroxides into non-toxic lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, thus highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide screens and a series of genetic, genomic, and quantitative imaging approaches, we identify the SWI-SNF ATPases BRM and BRG1 as ferroptosis suppressors. Mechanistically, they directly bind to and catalytically increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output. This primes cells to counter lipid peroxidation and confers resistance to GPX4 inhibition and ferroptosis. Importantly, we demonstrate that the BRM/BRG1-ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1-mutant lung cancer cells on BRM, especially in lines that are less sensitive to BRM inhibition or degradation. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
2024-09-22 | GSE266343 | GEO
Project description:Ferroptosis is an iron-dependent cell death mechanism characterized by an accumulation of toxic lipid peroxides and membrane rupture. The glutathione dependent enzyme, GPX4 (glutathione peroxidase 4), prevents ferroptosis by reducing these lipid peroxides into non-toxic lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, thus highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide screens and a series of genetic, genomic, and quantitative imaging approaches, we identify the SWI-SNF ATPases BRM and BRG1 as ferroptosis suppressors. Mechanistically, they directly bind to and catalytically increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output. This primes cells to counter lipid peroxidation and confers resistance to GPX4 inhibition and ferroptosis. Importantly, we demonstrate that the BRM/BRG1-ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1-mutant lung cancer cells on BRM, especially in lines that are less sensitive to BRM inhibition or degradation. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
2024-07-01 | GSE245243 | GEO
Project description:Ferroptosis is an iron-dependent cell death mechanism characterized by an accumulation of toxic lipid peroxides and membrane rupture. The glutathione dependent enzyme, GPX4 (glutathione peroxidase 4), prevents ferroptosis by reducing these lipid peroxides into non-toxic lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, thus highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide screens and a series of genetic, genomic, and quantitative imaging approaches, we identify the SWI-SNF ATPases BRM and BRG1 as ferroptosis suppressors. Mechanistically, they directly bind to and catalytically increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output. This primes cells to counter lipid peroxidation and confers resistance to GPX4 inhibition and ferroptosis. Importantly, we demonstrate that the BRM/BRG1-ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1-mutant lung cancer cells on BRM, especially in lines that are less sensitive to BRM inhibition or degradation. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
2024-09-22 | GSE245239 | GEO