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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116668 | GEO | 2019/08/23

REPOSITORIES: GEO