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

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

doi:10.15252/emmm.201708478

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.

Highlights

The majority of prostate cancers are dependent on androgens and activation of the androgen receptor (AR) for growth and survival, and androgen deprivation therapy remains the mainstay of treatment for advanced prostate cancer (Watson et al, 2015)
By treating AR-positive prostate cancer C4-2 cells with the commonly used pan class I/II HDAC inhibitors (HDACIs) trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), panobinostat (LBH589), and HDAC6-selective inhibitor tubastatin A, we demonstrated that these pan class I/II HDACIs, but not tubastatin A completely inhibited AKT phosphorylation at serine 473 (S473) and T308 (Fig 1A)
We provided evidence that inhibition of de novo protein synthesis by CHX failed to have overt effect on class I/II HDACI-induced suppression of AKT phosphorylation in prostate cancer cells and the drug effect appears to be an immediate event (30 min post-treatment). These findings suggest that inhibition of AKT phosphorylation by class I/II HDACIs is not primarily mediated by the genomic effect of these HDACIs in the nucleus of prostate cancer cells

Summary

Introduction

The majority of prostate cancers are dependent on androgens and activation of the androgen receptor (AR) for growth and survival, and androgen deprivation therapy remains the mainstay of treatment for advanced prostate cancer (Watson et al, 2015). The PI3K/ AKT pathway is often aberrantly activated due to frequent deletion or mutation of the PTEN tumor suppressor gene and activation mutations in PIK3CA and AKT1 genes during prostate tumorigenesis and progression (Cancer Genome Atlas Research Network, 2015, Robinson et al, 2015), representing another key actionable target. Both patient data analysis and pre-clinical animal model studies invariably show that loss of PTEN promotes enhanced AKT activity and reduced AR signaling and that inhibition of AKT results in AR activation while blockade of AR function increases AKT activities (Carver et al, 2011; Mulholland et al, 2011), stressing the a 2018 The Authors. HDAC inhibitors (HDACIs) have been developed for cancer therapy (Dokmanovic et al, 2007), supporting the critical oncogenic role of HDACs in tumorigenesis

Methods

Results

Conclusion