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

Yuqian Yan, Jian An, Yinhui Yang, Di Wu, Yang Bai, William Cao, Linlin Ma, Junhui Chen, Zhendong Yu, Yundong He, Xin Jin, Yunqian Pan, Tao Ma, Shangqian Wang, Xiaonan Hou, Saravut (John) Weroha, Robert Jeffrey Karnes, Jun Zhang, Jennifer J Westendorf, Liguo WangYu Chen, Wanhai Xu, Runzhi Zhu, Dejie Wang, Haojie Huang

Research output: Contribution to journalArticle

12 Scopus citations


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.

Original languageEnglish (US)
JournalEMBO Molecular Medicine
StateAccepted/In press - Jan 1 2018



  • AKT phosphorylation
  • Androgen receptor
  • HDAC3
  • Prostate cancer
  • RGFP966

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Yan, Y., An, J., Yang, Y., Wu, D., Bai, Y., Cao, W., Ma, L., Chen, J., Yu, Z., He, Y., Jin, X., Pan, Y., Ma, T., Wang, S., Hou, X., Weroha, S. J., Karnes, R. J., Zhang, J., Westendorf, J. J., ... Huang, H. (Accepted/In press). Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201708478