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Dissecting the interface between ARID1A and mRNA translation in bladder cancer

ABSTRACT: Dissecting the interface between ARID1A and mRNA translation in bladder cancer

PROVIDER: PRJNA830450 | ENA |

REPOSITORIES: ENA

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Dissecting the interface between ARID1A and mRNA translation in bladder cancer (Polysome)

Project description:Dissecting the interface between ARID1A and mRNA translation in bladder cancer (Polysome)

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Dissecting the interface between ARID1A and mRNA translation in bladder cancer (CUT&Tag)

Project description:Dissecting the interface between ARID1A and mRNA translation in bladder cancer (CUT&Tag)

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Dissecting the interface between ARID1A and mRNA translation in bladder cancer (CUT&Tag)

Project description:Chromatin remodeling and protein synthesis are tightly regulated processes that impact gene expression and cellular phenotypes. However, it is unknown if these two regulatory mechanisms are linked or exert independent effects in normal epithelial physiology and disease states. We have uncovered a new functional relationship between the chromatin remodeler ARID1A and mRNA translation elongation that is involved in maintaining cellular fitness in the context of bladder carcinogenesis. Loss of ARID1A triggers inhibition of the translation elongation factor eEF2 and ribosome accumulation, which results in a reduction in protein synthesis. In the setting of ARID1A deficiency the bladder carcinogen BBN induces DNA damage and cell death without impacting cancer initiation. As such, ARID1A is necessary for tumorigenesis. Remarkably, restoration of translation elongation through eEF2 is sufficient to initiate transformation in the context of ARID1A loss. However, dependence on ARID1A for transformation appears to be context specific, as loss of ARID1A after tumor establishment is sufficient for cancer progression.

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Dissecting the interface between ARID1A and mRNA translation in bladder cancer (Polysome)

2023-03-13 | GSE174283 | GEO

Effect of EZH2 inhibition on ARID1A mutant bladder cancer cell lines

Project description:ARID1A, a subunit of SWI/SNF chromatin remodeling complex. SWI/SNF complex can regulate expression of genes involved in vital biological processes such as cell cycle, DNA damage repair and development. ARID1A is known to have high mutation rate in human cancers including bladder cancer, leading to its loss of function. Publicly available whole exome sequencing data for muscle invasive and non-muscle invasive bladder cancers, show fraction of tumors with truncated ARID1A. Thus identifying therapeutic strategies for ARID1A mutant cancers is of high importance. EZH2, a histone methyltransferase is known to over-express and play pivotal role in aggressive bladder cancer. Our preliminary studies show that treatment of EZH2 inhibitor (GSK126) on ARID1A mutant bladder cancer cells significantly reduced cancer cell viability, invasion and colony formation relative to wild type ARID1A containing cells. Here, we performed microarray experiments to assess the effect of EZH2 inhibitor on global transcriptome of both ARID1A mutant and wild type bladder cancer cell line.

2023-05-01 | GSE150249 | GEO

Dissecting the interface between ARID1A and mRNA translation in bladder cancer

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

2023-03-13 | GSE201222 | GEO

Transcriptomic profiling for differential gene expression in ARID1A-wt and ARID1A-deficient bladder cancer cells with and without GSK126 (an EZH2 inhibitor) treatment

Project description:Metastatic urothelial carcinoma of the bladder is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A inactivating mutations present in 20% of tumors. EZH2 is a histone methyltransferase that acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in over 20% of bladder cancers. Here we show that ARID1A-mutant tumors are more sensitive to EZH2 inhibition than ARID1A-wild-type tumors. Mechanistic studies reveal that: 1) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a non-canonical PI3K regulatory subunit PIK3R3, and: 2) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, an inhibitor protein of PI3K signaling. Thus, our studies suggest that a subset of bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K, and reveal novel mechanistic insights into the role of non-canonical PI3K constituents in bladder cancer biology.

2022-08-22 | GSE183777 | GEO

Epigenomic change of ARDI1A mutant bladder cancer cell line treated with CPI-0209 or induced ARID1A expression

Project description:Advanced bladder cancer remains a difficult cancer to treat, and for the majority of patients, current standard treatments ultimately prove ineffective. These tumors frequently harbor mutations in the BAF complex subunit ARID1A, which has been reported to confer sensitivity to EZH2 inhibition in several tumor types. Here we describe the generation of CPI-0209, a best-in-class, orally available EZH2 inhibitor. We show that mutant bladder cancer lines harboring ARID1A loss of function (LOF) mutations are preferentially sensitive to inhibition of EZH2. Treatment with CPI-0209 not only elicits a significant monotherapeutic response in ARID1A mutant models, it also outperforms cisplatin and improves response in chemo-resistant models. These findings shine light on new therapeutic opportunities for patients with advanced urothelial carcinoma.

2024-06-26 | GSE176477 | GEO

Transcriptomic change of ARDI1A mutant bladder cancer cell line treated with CPI-0209 or induced ARID1A expression

2024-06-26 | GSE176358 | GEO

ARID1A-deficient Bladder Cancer is Dependent on PI3K Signaling, and can be Targeted via EZH2 and/or PI3K Pharmacologic Inhibition: Therapeutic Implications

Project description:ARID1A-mutant bladder cancer is dependent on PI3K signaling and is sensitive to EZH2 and/or PI3K inhibition. Clinical trials in molecularly selected patients should be considered.

2022-08-22 | GSE203033 | GEO

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