Dual inhibition of AKT ‐m TOR and AR signaling by targeting HDAC 3 in PTEN ‐ or SPOP ‐mutated prostate cancer

Abstract AKT ‐ mTOR and androgen receptor ( AR ) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC 3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC 3 facilitates lysine‐63‐chain polyubiquitination and phosphorylation of AKT , and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC 3 interaction with the scaffold protein APPL 1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC 3 using a selective HDAC 3 inhibitor RGFP 966 inhibits growth of both PTEN ‐deficient and SPOP ‐mutated prostate cancer cells in culture, patient‐derived organoids and xenografts in mice. Our study identifies HDAC 3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by single‐agent targeting of HDAC 3 in prostate cancer.