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

Authors: 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.; Wang, L.; Chen, Y.; Xu, W.; Zhu, R.; Wang, D.; Huang, H.
Article Title: Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 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 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. © 2018 The Authors. Published under the terms of the CC BY 4.0 license
Keywords: prostate cancer; androgen receptor; akt phosphorylation; hdac3; rgfp966
Journal Title: EMBO Molecular Medicine
Volume: 10
Issue: 4
ISSN: 1757-4676
Publisher: Wiley Blackwell  
Date Published: 2018-04-01
Start Page: e8478
Language: English
DOI: 10.15252/emmm.201708478
PROVIDER: scopus
PMCID: PMC5887910
PUBMED: 29523594
Notes: Article -- Export Date: 1 May 2018 -- Source: Scopus
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MSK Authors
  1. Yu Chen
    67 Chen
  2. Shangqian   Wang
    13 Wang