In the present study, we identify ARID4B as a regulator of the PTEN-PI3K pathway by functioning as a transcriptional activator of PIK3CA and PIK3R2. Importantly, we demonstrate that ARID4B is required for initiation and progression of PTEN-deficient prostate cancer, suggesting ARID4B is a potential therapeutic target for prostate cancer harboring PTEN mutations. This evidence concerns the gene PIK3CG and Familial prostate cancer.