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Int J Cancer. 2019 Jul 15;145(2):415-426. doi: 10.1002/ijc.32118. Epub 2019 Feb 12.

Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer.

Liu Q1,2,3, Wang G4,5, Li Q1,2,6,7, Jiang W1, Kim JS1, Wang R1, Zhu S1, Wang X8,9, Yan L1,2, Yi Y1,7,10,11, Zhang L1, Meng Q1,7, Li C1,6,7, Zhao D4,5, Qiao Y8,9, Li Y8,9, Gursel DB12,13, Chinnaiyan AM8,9,14,15,16, Chen K4,5,17, Cao Q1,7,18.

Author information

1
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX.
2
Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
3
Department of Urology, The Second Xiangya Hospital of Central South University, Hunan, China.
4
Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX.
5
Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, NY.
6
Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
7
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL.
8
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI.
9
Department of Pathology, University of Michigan, Ann Arbor, MI.
10
Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, China.
11
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
12
Pathology Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL.
13
Pathology Department, Feinberg School of Medicine, Northwestern University, Chicago, IL.
14
Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI.
15
Department of Urology, University of Michigan, Ann Arbor, MI.
16
Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI.
17
Institutes for Academic Medicine, Houston Methodist Hospital, Houston, TX.
18
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL.

Abstract

Polycomb group proteins are important epigenetic regulators for cell proliferation and differentiation, organ development, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including Enhancer of zeste homolog 2 (EZH2), promote proliferation, migration, invasion and metastasis of cancer cells, as well as self-renewal of cancer stem cells. In our study, we report that EZH2 and embryonic ectoderm development (EED) indicate respective direct interaction with androgen receptor (AR). In the context of AR-positive prostate cancer, EZH2 and EED regulate AR expression levels and AR downstream targets. More importantly, we demonstrate that targeting EZH2 with the small-molecule inhibitor astemizole in cancer significantly represses the EZH2 and AR expression as well as the neoplastic capacities. These results collectively suggest that pharmacologically targeting EZH2 might be a promising strategy for advanced prostate cancer.

KEYWORDS:

EED; EZH2; androgen receptor; astemizole; prostate cancer

PMID:
30628724
DOI:
10.1002/ijc.32118

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