KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer

Abstract Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we an...

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Main Authors: Zhi Cao, Xiaolei Shi, Feng Tian, Yu Fang, Jason Boyang Wu, Stefan Mrdenovic, Xinwen Nian, Jin Ji, Huan Xu, Chen Kong, Yalong Xu, Xi Chen, Yuhua Huang, Xuedong Wei, Yongwei Yu, Bo Yang, Leland W. K. Chung, Fubo Wang
Format: Article
Language:English
Published: Nature Publishing Group 2021-01-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-020-03354-4
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spelling doaj-d638d6981b494bdf804b0c1b96a7bb4f2021-01-10T12:07:36ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111510.1038/s41419-020-03354-4KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancerZhi Cao0Xiaolei Shi1Feng Tian2Yu Fang3Jason Boyang Wu4Stefan Mrdenovic5Xinwen Nian6Jin Ji7Huan Xu8Chen Kong9Yalong Xu10Xi Chen11Yuhua Huang12Xuedong Wei13Yongwei Yu14Bo Yang15Leland W. K. Chung16Fubo Wang17Department of Urology, Changhai Hospital, Navy Medical UniversityDepartment of Urology, Changhai Hospital, Navy Medical UniversityDepartment of Urology, The Eighth People’s Hospital of ShanghaiDepartment of Urology, Changhai Hospital, Navy Medical UniversityDepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityUro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical CenterDepartment of Urology, Changhai Hospital, Navy Medical UniversityDepartment of Urology, Changhai Hospital, Navy Medical UniversityDepartment of Urology, Changhai Hospital, Navy Medical UniversityDepartment of Traditional Chinese Medicine, New Jiangwan City Community Health Service CentreDepartment of Urology, Changhai Hospital, Navy Medical UniversityDepartment of Urology, Changhai Hospital, Navy Medical UniversityDepartment of Urology, The First Affiliated Hospital of Soochow UniversityDepartment of Urology, The First Affiliated Hospital of Soochow UniversityDepartment of Pathology, Changhai Hospital, Navy Medical UniversityDepartment of Urology, Changhai Hospital, Navy Medical UniversityUro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical CenterDepartment of Urology, Changhai Hospital, Navy Medical UniversityAbstract Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.https://doi.org/10.1038/s41419-020-03354-4
collection DOAJ
language English
format Article
sources DOAJ
author Zhi Cao
Xiaolei Shi
Feng Tian
Yu Fang
Jason Boyang Wu
Stefan Mrdenovic
Xinwen Nian
Jin Ji
Huan Xu
Chen Kong
Yalong Xu
Xi Chen
Yuhua Huang
Xuedong Wei
Yongwei Yu
Bo Yang
Leland W. K. Chung
Fubo Wang
spellingShingle Zhi Cao
Xiaolei Shi
Feng Tian
Yu Fang
Jason Boyang Wu
Stefan Mrdenovic
Xinwen Nian
Jin Ji
Huan Xu
Chen Kong
Yalong Xu
Xi Chen
Yuhua Huang
Xuedong Wei
Yongwei Yu
Bo Yang
Leland W. K. Chung
Fubo Wang
KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer
Cell Death and Disease
author_facet Zhi Cao
Xiaolei Shi
Feng Tian
Yu Fang
Jason Boyang Wu
Stefan Mrdenovic
Xinwen Nian
Jin Ji
Huan Xu
Chen Kong
Yalong Xu
Xi Chen
Yuhua Huang
Xuedong Wei
Yongwei Yu
Bo Yang
Leland W. K. Chung
Fubo Wang
author_sort Zhi Cao
title KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer
title_short KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer
title_full KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer
title_fullStr KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer
title_full_unstemmed KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer
title_sort kdm6b is an androgen regulated gene and plays oncogenic roles by demethylating h3k27me3 at cyclin d1 promoter in prostate cancer
publisher Nature Publishing Group
series Cell Death and Disease
issn 2041-4889
publishDate 2021-01-01
description Abstract Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.
url https://doi.org/10.1038/s41419-020-03354-4
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