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Targeting USP8 Causes Synthetic Lethality through Degradation of FGFR2 in ARID1A-Deficient Ovarian Clear Cell Carcinoma

ABSTRACT: Targeting USP8 Causes Synthetic Lethality through Degradation of FGFR2 in ARID1A-Deficient Ovarian Clear Cell Carcinoma

PROVIDER: PRJNA1140249 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29999186_1.fastq.gz	Fastqsanger.gz
	SRR29999186_2.fastq.gz	Fastqsanger.gz
	SRR29999187_1.fastq.gz	Fastqsanger.gz
	SRR29999187_2.fastq.gz	Fastqsanger.gz
	SRR29999188_1.fastq.gz	Fastqsanger.gz

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Targeting USP8 Causes Synthetic Lethality through Degradation of FGFR2 in ARID1A-Deficient Ovarian Clear Cell Carcinoma

Project description:Over half of ovarian clear cell carcinoma (OCCC) cases exhibit deficiencies in the ARID1A gene, a chromatin remodeling complex component. OCCC is resistant to chemotherapy and challenging to treat, necessitating new drug treatment strategies. This study used a publicly available dependency factor database to identify synthetic lethal targets for ARID1A-deficient cancer. The DepMap portal was used to identify genes on which ARID1A-deficient cancer cell lines are highly dependent. Our analysis limited to ovarian cancer cell lines only identified the deubiquitinating enzyme USP8 as a synthetic lethal target in ARID1A-deficient OCCC cancer cell lines and mouse xenograft models. In addition, USP8 inhibitors were more selective for ARID1A-deficient cells than existing candidate drugs used in promising clinical trials for ARID1A-deficient cancers. Suppression of USP8 in ARID1A-deficient cells led to degradation of FGFR2 via the proteasome. Deficiency of ARID1A causes abnormalities in the STAT3 pathway, which is one of the downstream pathways of FGFR2, but suppression of USP8 attenuates phosphorylation of STAT3 pT705 and induces apoptosis. Taken together, the data suggest that USP8 is a novel therapeutic target for ARID1A-deficient OCCC and that it suppresses FGFR2-STAT3 signaling.

2025-03-12 | GSE273150 | GEO

Targeting USP8 causes synthetic lethality through degradation of FGFR2 in ARID1A-deficient ovarian clear cell carcinoma.

Project description:Over half of ovarian clear cell carcinoma (OCCC) cases exhibit deficiencies in the ARID1A gene, a chromatin remodeling complex component. OCCC is resistant to chemotherapy and challenging to treat, necessitating new drug treatment strategies. This study used a publicly available dependency factor database to identify synthetic lethal targets for ARID1A-deficient cancer. The DepMap portal was used to identify genes on which ARID1A-deficient cancer cell lines are highly dependent. Our analysis limited to ovarian cancer cell lines only identified the deubiquitinating enzyme USP8 as a synthetic lethal target in ARID1A-deficient OCCC cancer cell lines and mouse xenograft models. In addition, USP8 inhibitors were more selective for ARID1A-deficient cells than existing candidate drugs used in promising clinical trials for ARID1A-deficient cancers. Suppression of USP8 in ARID1A-deficient cells led to degradation of FGFR2 via the proteasome. Deficiency of ARID1A causes abnormalities in the STAT3 pathway, which is one of the downstream pathways of FGFR2, but suppression of USP8 attenuates phosphorylation of STAT3 pT705 and induces apoptosis. Taken together, our data suggest that USP8 is a novel therapeutic target for ARID1A-deficient OCCC and that USP8 inhibitors suppress FGFR2-STAT3 signaling.

| S-EPMC11903656 | biostudies-literature

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

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

ARID1A KLF5 synthetic lethality CRISPR screen in U2OS cells

Project description:ARID1A KLF5 synthetic lethality CRISPR screen in U2OS cells

| PRJEB75512 | ENA

Transcriptome profiling of wild-type (WT) and USP8 knockout (KO) CT26 cell lines

Project description:USP8 is one of DUBs and is frequently overexpressed or gain-of-function mutated in multiple types of human cancer. Importantly, USP8 has been identified as an immunomodulatory DUB as T cell-specific Usp8 deficiency disrupts regulatory T cell functions, leading to recruiting abundant CD8+ T cells in colons and resulting in the inflammatory bowel disease in mice. However, whether targeting USP8 can enhance anti-tumor immunity has not been reported. To further explore the physiological function of USP8, we performed the transcriptomic analysis to comprehensively understand which signaling pathways are mainly regulated by USP8 in cancer cells. Usp8 WT and KO CT26 cells were harvested for RNA-sequencing (RNA-seq).

2022-02-14 | GSE164558 | GEO

Epigenetic synthetic lethality in ovarian clear cell carcinoma: EZH2 and ARID1A mutations.

Project description:The components of the Switch/Sucrose non-fermentable (SWI/SNF) complex are mutated in approximately 20% of human cancers. The A/T-rich interacting domain 1A (ARID1A) subunit has one of the highest mutation rates. Most notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas (OCCCs). We reported that inhibition of enhancer of zeste homology 2 (EZH2) is synthetically lethal in ARID1A-mutated OCCC.

| S-EPMC4845188 | biostudies-other

USP8 coordinates ESCRT-mediated membrane repair, xenophagy, and oxidative stress responses during Mycobacterium tuberculosis infection

Project description:We show that USP8 colocalizes with intracellular Mtb, recognizes phagosomal membrane damage, and is required for ESCRT-dependent membrane repair. Furthermore, USP8 regulates the NRF2-dependent antioxidant signature. Taken together, our study shows a central role of USP8 in promoting intracellular growth of Mtb by coordinating phagosomal membrane repair, ubiquitin-driven selective autophagy, and the oxidative stress response.

2024-08-07 | GSE240372 | GEO

Synthetic lethality between ARID1A mutation and HDAC2 inhibition in ovarian cancer

Project description:Synthetic lethality between ARID1A mutation and HDAC2 inhibition in ovarian cancer

| PRJNA419301 | ENA

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.

2018-03-09 | GSE107201 | GEO

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