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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens Homo

PROVIDER: GSE228179 | 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]

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

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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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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]

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Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.

Project description:The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.

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Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells.

Project description:ARID1A, a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor with a high frequency of inactivating mutations in many cancers. Therefore, ARID1A deficiency has been exploited therapeutically for treating cancer. Here we show that ARID1A has a synthetic lethal interaction with aurora kinase A (AURKA) in colorectal cancer (CRC) cells. Pharmacological and genetic perturbations of AURKA selectively inhibit the growth of ARID1A-deficient CRC cells. Mechanistically, ARID1A occupies the AURKA gene promoter and negatively regulates its transcription. Cells lacking ARID1A show enhanced AURKA transcription, which leads to the persistent activation of CDC25C, a key protein for G2/M transition and mitotic entry. Inhibiting AURKA activity in ARID1A-deficient cells significantly increases G2/M arrest and induces cellular multinucleation and apoptosis. This study shows a novel synthetic lethality interaction between ARID1A and AURKA and indicates that pharmacologically inhibiting the AURKA-CDC25C axis represents a novel strategy for treating CRC with ARID1A loss-of-function mutations.

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Therapeutic Role of Synthetic Lethality in ARID1A-Deficient Malignancies

Project description: Not available

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Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.

Project description:Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

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Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma.

Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify new insights in HCC to develop novel strategies for HCC management.MethodsThe role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, xenograft model, DEN (Diethylnitrosamine) induced mice liver cancer model with WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, western blotting, comet assay, and Immunofluorescence.ResultsHigh expression of WIP1 is associated with the poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation. Besides, WIP1 knockout retarded DEN induced mice hepato-carcinogenesis. Mechanically, WIP1 inhibition induced DNA damage by increasing H2AX phosphorylation (γH2AX). Therefore, suppression of WIP1 and PARP induced synthetic lethality in HCC in vitro and in vivo by augmenting DNA damage.ConclusionWIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair alone or in combination with PARP inhibition might be a reasonable strategy for HCC management. Video abstract.

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