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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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Identification of the PTEN-ARID4B-PI3K pathway reveals the dependency on ARID4B by PTEN-deficient prostate cancer
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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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Journal Article
Identification of the PTEN-ARID4B-PI3K pathway reveals the dependency on ARID4B by PTEN-deficient prostate cancer
2019
Overview
PTEN
is frequently mutated in prostate cancer. The tumor suppressor function of PTEN is attributed to its lipid phosphatase activity that counters PI3K action. Here, we report a PTEN-ARID4B-PI3K axis in which PTEN inhibits expression of
ARID4B
, while ARID4B is a transcriptional activator of the PI3K subunit genes
PIK3CA
and
PIK3R2
that are crucial for activation of the PI3K/AKT pathway. Reciprocal binding of ARID4B and histone H1 to the
PIK3CA
and
PIK3R2
promoters modulates chromatin condensation, suggesting a mechanism by which ARID4B activates these promoters. Functional analyses reveals that ARID4B is required for prostate tumorigenesis when PTEN is deficient. The biological significance is further substantiated by the existence of a
PTEN
/
ARID4B
/
PIK3CA
three-gene signature that improves the predictive power for prostate cancer recurrence in patients. In summary, we identify ARID4B as a master regulator in the PTEN-PI3K pathway, thus providing a potential therapeutic target for prostate cancer carrying
PTEN
mutations.
The identification of synthetic essential genes of PTEN is of therapeutic potential for PTEN-deficient prostate cancers. Here, the authors show that ARID4B is a synthetic essential gene in these cancers in which deficiency of PTEN prompts the AKT-ARID4B feedback loop required for activation of the PI3K-AKT signaling pathway.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
1-Phosphatidylinositol 3-kinase
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/ Animals
/ Antigens, Neoplasm - genetics
/ Antigens, Neoplasm - metabolism
/ Humanities and Social Sciences
/ Humans
/ Lipids
/ Male
/ Mutation
/ Neoplasm Proteins - genetics
/ Neoplasm Proteins - metabolism
/ Phosphatidylinositol 3-Kinases - metabolism
/ Prostatic Neoplasms - genetics
/ Prostatic Neoplasms - metabolism
/ PTEN Phosphohydrolase - genetics
/ PTEN Phosphohydrolase - metabolism
/ Science
