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. The gene discussed is PTEN; the disease is prostate carcinoma.