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CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma [RNA-seq]

ABSTRACT: CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma [RNA-seq]

PROVIDER: PRJNA852588 | ENA |

REPOSITORIES: ENA

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CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma [CRISPR screen]

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

CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma [RNA-seq]

2025-06-24 | GSE206906 | GEO

CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma

Project description:CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma

| PRJNA852587 | ENA

CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma [CRISPR screen]

Project description:CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma [CRISPR screen]

| PRJNA852589 | ENA

CRISPR screens uncover CRTC3 as a regulator of IFN-γ induced ferroptosis in hepato-cellular carcinoma

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

2025-06-24 | GSE206907 | GEO

CRISPR screens uncover protective effect of PSTK to targeted therapy induced ferroptosis in hepatocellular carcinoma

Project description:CRISPR screens uncover protective effect of PSTK to targeted therapy induced ferroptosis in hepatocellular carcinoma

| PRJNA755280 | ENA

CRISPR screens uncover protective effect of PSTK to targeted therapy induced ferroptosis in hepatocellular carcinoma

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

Transcript profiling in WT, CRTC3 KO and CRTC3-rescued B16F1 cells.

Project description:Triggering of cAMP and mitogen-activated (MAPK) pathways in response to hormonal and growth factor cues promotes melanocyte pigmentation and survival in part through induction of the master regulator MITF by cAMP-responsive factor CREB. We examined the role of CREB coactivators (CRTC1-3) in transduction of cAMP and MAPK signals in melanocytes. We found that CRTC3 knock-out in mice and B16F1 melanoma cells decreases pigmentation by directly regulating the expression of the melanosomal transporter OCA2. In addition to effects of cAMP, CRTC3 activation was also promoted by ERK1/2-mediated phosphorylation at Ser391; amounts of phosphorylated CRTC3-S391 were constitutively elevated in human melanoma cells expressing mutated BRAF or NF1. Knock-out of CRTC3 in A375 melanoma cells impaired their anchorage-independent growth, migration and invasiveness, whereas CRTC3 over-expression increased survival in response to BRAF inhibition by vemurafenib. Analysis of spontaneous CRTC3 mutations in melanomas reveals that increased activity of this co-activator associates with reduced patient survival. Our results highlight the importance of CRTC3 in pigmentation and melanoma progression.

2022-04-12 | GSE154115 | GEO

Expression data from primary astrocyte cell in CRTC3 KO and WT mice

Project description:CRTC3 is CREB regulated transcriptional co-activators and prominently expressed in astrocyte cells. CRTC3 plays a specific role in determining the social heirarchical ranking in mice by confirming social rank test in CRTC3 KO mice. Loss of CRTC3 in astrocyte induced neuronal change and caused exchanging protein expression pattern. We used microarrays to determine the astrocyte-derived factors that were regulated by CRTC3 and related with social dominance behaviours of CRTC3 KO mice. We identifed distinct factor of down-regulated gene during primary astrocyte cell in CRTC3 KO.

2023-09-17 | GSE222741 | GEO

CRISPR activation screens identify the SWI-SNF ATPases as suppressors of ferroptosis

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

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