Abstract
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.
Highlights
PTEN is frequently mutated in prostate cancer
Using two prostate cancer gene expression datasets in the Oncomine database[23,26], we found that expression of ARID4B was significantly increased in prostate carcinoma (PCa) compared to normal prostate glands (Supplementary Fig. 1b)
Patients expressing higher levels of ARID4B had a significantly increased risk of prostate-specific antigen recurrence in two datasets[27,28] (Supplementary Fig. 1d). These results indicate that expression of ARID4B positively correlates with prostate cancer development, and tumor recurrence is sensitive to higher levels of ARID4B expression
Summary
PTEN is frequently mutated in prostate cancer. The tumor suppressor function of PTEN is attributed to its lipid phosphatase activity that counters PI3K action. We identify ARID4B as a master regulator in the PTEN-PI3K pathway, providing a potential therapeutic target for prostate cancer carrying PTEN mutations. Loss of the tumor suppressor gene PTEN is a frequent genetic alteration in prostate cancers, and many late-stage prostate cancers showed altered activity in the PTEN-PI3K pathway[1,2]. The emerging concept of synthetic essentiality in cancer describes cancers with specific tumor suppressor deficiencies that depend on expression of synthetic-essential genes Targeting such genes may be a promising alternative treatment approach for cancers that acquire loss-of-function mutations on tumor suppressor genes[3]. We identify ARID4B as a regulator of the PTEN-PI3K pathway by functioning as a transcriptional activator of PIK3CA and PIK3R2. We demonstrate that ARID4B is required for initiation and progression of PTENdeficient prostate cancer, suggesting ARID4B is a potential therapeutic target for prostate cancer harboring PTEN mutations
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