Our findings provide mechanistic explanation as to how AKT phosphorylation and AR expression is regulated by HDAC3 and highlight that dual inhibition of AKT‐mTOR and AR by a single agent is clinically achievable by using small molecule inhibitors of HDAC3 in prostate cancer, especially those with PTEN deletion or SPOP mutation. This evidence concerns the gene AKT1 and Familial prostate cancer.