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 pr...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2018-04-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201708478 |
| _version_ | 1797283987367919616 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yuqian Yan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:39:33Z |
| format | Article |
| id | doaj.art-fe77ca9d430249659565d1429f2f9aba |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:39:33Z |
| publishDate | 2018-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-fe77ca9d430249659565d1429f2f9aba2024-03-02T16:06:46ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-04-01104n/an/a10.15252/emmm.201708478Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancerYuqian Yan0Jian An1Yinhui Yang2Di Wu3Yang Bai4William Cao5Linlin Ma6Junhui Chen7Zhendong Yu8Yundong He9Xin Jin10Yunqian Pan11Tao Ma12Shangqian Wang13Xiaonan Hou14Saravut John Weroha15R Jeffrey Karnes16Jun Zhang17Jennifer J Westendorf18Liguo Wang19Yu Chen20Wanhai Xu21Runzhi Zhu22Dejie Wang23Haojie Huang24Department of Gastroenterology Jiangxi Institute of Gastroenterology and Hepatology First Affiliated Hospital of Nanchang University Nanchang Jiangxi ChinaDepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Minimally Invasive Intervention Peking University Shenzhen Hospital Shenzhen Guangdong ChinaCentral Laboratory Peking University Shenzhen Hospital Shenzhen Guangdong ChinaDepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biomedical Statistics and Informatics Mayo Clinic Cancer Center Rochester MN USAHuman Oncology and Pathogenesis Program Memorial Sloan‐Kettering Cancer Center New York NY USADepartment of Oncology Mayo Clinic College of Medicine Rochester MN USADepartment of Oncology Mayo Clinic College of Medicine Rochester MN USADepartment of Urology Mayo Clinic College of Medicine Rochester MN USADepartment of Laboratory Medicine and Pathology Mayo Clinic College of Medicine Rochester MN USADepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USADepartment of Biomedical Statistics and Informatics Mayo Clinic Cancer Center Rochester MN USAHuman Oncology and Pathogenesis Program Memorial Sloan‐Kettering Cancer Center New York NY USADepartment of Urology The Fourth Hospital of Harbin Medical University Harbin Heilongjiang ChinaCenter for Cell Therapy The Affiliated Hospital of Jiangsu University Zhenjiang Jiangsu ChinaDepartment of Gastroenterology Jiangxi Institute of Gastroenterology and Hepatology First Affiliated Hospital of Nanchang University Nanchang Jiangxi ChinaDepartment of Biochemistry and Molecular Biology Mayo Clinic College of Medicine Rochester MN USAAbstract 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.https://doi.org/10.15252/emmm.201708478AKT phosphorylationandrogen receptorHDAC3prostate cancerRGFP966 |
| spellingShingle | 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 Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer EMBO Molecular Medicine AKT phosphorylation androgen receptor HDAC3 prostate cancer RGFP966 |
| title | Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer |
| title_full | Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer |
| title_fullStr | Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer |
| title_full_unstemmed | Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer |
| title_short | Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer |
| title_sort | dual inhibition of akt mtor and ar signaling by targeting hdac3 in pten or spop mutated prostate cancer |
| topic | AKT phosphorylation androgen receptor HDAC3 prostate cancer RGFP966 |
| url | https://doi.org/10.15252/emmm.201708478 |
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