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A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE116670 | GEO | 2019/08/23

REPOSITORIES: GEO

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A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer [ChIP-seq]

Project description:Phosphatase and tensin homologue (PTEN) is the most frequently mutated tumor suppressor gene in human prostate cancer. Synthetic essentiality is defined as cancer that harbors a specific tumor suppressor deficiency is dependent on synthetic-essential genes for the malignant phenotypes. Recently, targeting such synthetic-essential genes has become an attractive treatment approach for cancers that acquire loss-of-function mutations in tumor suppressor genes. Here, we show that AT-rich interaction domain 4B (ARID4B) functions as a synthetic-essential gene in prostate tumorigenesis driven by PTEN deficiency. This functional interaction between ARID4B and PTEN is recapitulated in the mouse model carrying prostate-specific deletions of Pten and Arid4b in which ablation of ARID4B attenuated prostate cancer progression elicited by loss of PTEN. Although the tumor suppressor function of PTEN is most attributed to its lipid phosphatase activity that counters the PI3K action in cytoplasm, we identified the PTEN-ARID4B-PI3K axis in which nuclear PTEN inhibits expression of ARID4B, while ARID4B serves as a transcriptional activator of the PI3K subunits PIK3CA and PIK3R2 to trigger the PI3K/AKT pathway. Our study further demonstrated that the reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation, indicating a mechanism by which ARID4B activates these promoters. Finally, a three-gene signature consisting of PTEN, ARID4B, and PI3K substantially improves the predictive power for tumor recurrence in human prostate cancer patients, underscoring the clinical significance of this newly identified PTEN-ARID4B-PI3K axis. These findings reveal a novel synthetic-essential relationship between ARID4B and PTEN, thus exposing a previously unidentified cancer-specific vulnerability, and supporting ARID4B as a potential therapeutic target for prostate cancer patients with PTEN mutations.

2019-08-23 | GSE116669 | GEO

A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer [RNA-seq]

2019-08-23 | GSE116668 | GEO

A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer

Project description:A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer

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A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer [RNA-seq]

Project description:A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer [RNA-seq]

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A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer [ChIP-seq]

Project description:A Novel PI3K Regulator, ARID4B, Presents Synthetic Essentiality in PTEN-deficient Prostate Cancer [ChIP-seq]

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Identification of the PTEN-ARID4B-PI3K pathway reveals the dependency on ARID4B by PTEN-deficient prostate cancer.

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Project description:PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NFkB activating protein (NKAP) and limits NFkB activation to suppress expression of PDHK1, a NFkB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.

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