Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer

EMBO Mol Med. 2018 Apr;10(4):e8478. doi: 10.15252/emmm.201708478.


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 HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine-63-chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. 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 HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN-deficient and SPOP-mutated prostate cancer cells in culture, patient-derived organoids and xenografts in mice. Our study identifies HDAC3 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 HDAC3 in prostate cancer.

Keywords: AKT phosphorylation; HDAC3; RGFP966; androgen receptor; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acrylamides / pharmacology
  • Animals
  • Blotting, Western
  • Genotype
  • HEK293 Cells
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phenylenediamines / pharmacology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligase Complexes


  • Acrylamides
  • Nuclear Proteins
  • Phenylenediamines
  • RGFP966
  • Receptors, Androgen
  • Repressor Proteins
  • SPOP protein, human
  • Spop protein, mouse
  • Ubiquitin-Protein Ligase Complexes
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • Histone Deacetylases
  • histone deacetylase 3