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 ofHdac3suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in thePtenknockout 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.
EMBO molecular medicine. 2018 Mar 09 [Epub ahead of print]
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, R Jeffrey Karnes, Jun Zhang, Jennifer J Westendorf, Liguo Wang, Yu Chen, Wanhai Xu, Runzhi Zhu, Dejie Wang, Haojie Huang
Department of Gastroenterology, Jiangxi Institute of Gastroenterology and Hepatology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA., Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China., Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China., Department of Biomedical Statistics and Informatics, Mayo Clinic Cancer Center, Rochester, MN, USA., Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA., Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA., Department of Urology, Mayo Clinic College of Medicine, Rochester, MN, USA., Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA., Department of Urology, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China., Center for Cell Therapy, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China ., Department of Gastroenterology, Jiangxi Institute of Gastroenterology and Hepatology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China ., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA .