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Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma [Cut&Run]

ABSTRACT: To further explore the mechanisms of glucose metabolic reprogramming in ARID1A deficiency HCC, we conducted multi-omics profilings in ARID1A deficient and wild type Hep3B cells.

ORGANISM(S): Homo

PROVIDER: GSE228175 | GEO | 2023/09/07

REPOSITORIES: GEO

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Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma [ATAC-Seq]

Project description:To further explore the mechanisms of glucose metabolic reprogramming in ARID1A deficiency HCC, we conducted multi-omics profilings in ARID1A deficient and wild type Hep3B cells.

2023-09-07 | GSE228176 | GEO

Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma

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

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Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma [Cut&Run]

Project description:Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma [Cut&Run]

| PRJNA948438 | ENA

Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma

Project description:Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma

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Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma [ATAC-Seq]

Project description:Targeting TCA cycle through Cuproptosis confers Synthetic Lethality to ARID1A Deficiency Hepatocellular Carcinoma [ATAC-Seq]

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PPP2R1A mutations cause ATR inhibitor synthetic lethality in ARID1A deficient ovarian clear cell carcinoma

Project description:Ovarian clear cell carcinoma (OCCC) is a cancer of unmet need characterized by ARID1A mutation. Prior work identified an ARID1A/ATR synthetic lethality, information that led to phase II clinical trials. Using genome-wide CRISPR-Cas9 mutagenesis and interference screens, we identified protein phosphatase 2A (PP2A) subunits, including PPP2R1A, as determinants of ATRi sensitivity in ARID1A mutant OCCC. Analysis of an OCCCs cohort indicated that >1/3 possessed both PPP2R1A and ARID1A loss-of-function mutations. CRISPR-prime editing demonstrated that oncogenic PPP2R1A p.R183 missense mutations enhance in vitro and in vivo ATRi sensitivity in ARID1A mutant OCCC. OCCC patients with both ARID1A and PPP2R1A mutations also showed clinical responses to ATRi in a phase II trial. Mechanistically, this synthetic lethal effect is dependent upon WNK1 kinase, which opposes PP2A function. This data suggests that co-occurrence of PPP2R1A and ARID1A mutations in OCCC should be assessed as a biomarker of ATRi response in on-going clinical trials.

2023-05-10 | PXD040422 | Pride

Synthetic lethality between ARID1A mutation and HDAC2 inhibition in ovarian cancer

Project description:ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most frequently mutated epigenetic regulators in human cancers. ARID1A is mutated in over 50% ovarian clear cell carcinoma, a disease currently has no effective therapy. Here we show that ARID1A-mutated ovarian cancer cells are selectively sensitive to inhibition of HDAC2 activity. HDAC2 interacts with EZH2 in an ARID1A status dependent manner. HDAC2 knockdown inhibits the growth of ARID1A inactivated by not proficient ovarian cancer cells. HDAC2 functions as a co-repressor of EZH2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1, an inhibitor of PI3K/AKT signaling, to inhibit proliferation and promote apoptosis. Indeed, a FDA-approved pan-HDAC inhibitor suberoylannilide hydroxamine (SAHA) significantly suppressed the growth and reduced the ascites of the ARID1A-inactivated ovarian cancers in both orthotopic and genetic mouse models. This correlated with a significant improvement of survival of mice bearing ARID1A-mutated ovarian cancers.

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Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress