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

Qipeng Liu; Guangyu Wang; Qiaqia Li; Weihua Jiang; Jung Sun Kim; Rui Wang; Sen Zhu; Xiaoju Wang; Lin Yan; Yang Yi; Lili Zhang; Qingshu Meng; Chao Li; Dongyu Zhao; Yuanyuan Qiao; Yong Li; Demirkan B. Gursel; Arul M. Chinnaiyan; Kaifu Chen; Qi Cao

doi:10.1002/ijc.32118

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

Qipeng Liu, Guangyu Wang, Qiaqia Li, Weihua Jiang, Jung Sun Kim, Rui Wang, Sen Zhu, Xiaoju Wang, Lin Yan, Yang Yi, Lili Zhang, Qingshu Meng, Chao Li, Dongyu Zhao, Yuanyuan Qiao, Yong Li, Demirkan B. Gursel, Arul M. Chinnaiyan, Kaifu Chen^*, Qi Cao

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

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.

Original language	English (US)
Pages (from-to)	415-426
Number of pages	12
Journal	International Journal of Cancer
Volume	145
Issue number	2
DOIs	https://doi.org/10.1002/ijc.32118
State	Published - Jul 15 2019

Funding

We appreciate the strong support from Dr. Anastasia K. Yocum, Dr. Leland W. Chang and Dr. J. Chad Brenner. We thank Johnique T. Atkins for comments and editing our study. We appreciate the support from Dr. Bella Shmaltsuyeva and Dr. Shanshan Zhang from Pathology Core Facility of Northwestern University. Houston Methodist Research Institute, Prostate Cancer Foundation (13YOUN007 to Q.C.), U.S. Department of Defense (W81XWH-15-1-0639 and W81XWH-17-1-0357 to Q.C.), American Cancer Society (TBE-128382 to Q.C.), and NIH/NCI (R01CA208257 to Q.C.); K.C. is supported in part by grants from NIH/NHLBI (R01CA208257, HL100397 and HL099997) and Department of Defense (W81XWH-17-1-0357);

Keywords

EED
EZH2
androgen receptor
astemizole
prostate cancer

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ijc.32118

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Liu, Q., Wang, G., Li, Q., Jiang, W., Kim, J. S., Wang, R., Zhu, S., Wang, X., Yan, L., Yi, Y., Zhang, L., Meng, Q., Li, C., Zhao, D., Qiao, Y., Li, Y., Gursel, D. B., Chinnaiyan, A. M., Chen, K., & Cao, Q. (2019). Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer. International Journal of Cancer, 145(2), 415-426. https://doi.org/10.1002/ijc.32118

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title = "Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer",

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",

author = "Qipeng Liu and Guangyu Wang and Qiaqia Li and Weihua Jiang and Kim, {Jung Sun} and Rui Wang and Sen Zhu and Xiaoju Wang and Lin Yan and Yang Yi and Lili Zhang and Qingshu Meng and Chao Li and Dongyu Zhao and Yuanyuan Qiao and Yong Li and Gursel, {Demirkan B.} and Chinnaiyan, {Arul M.} and Kaifu Chen and Qi Cao",

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year = "2019",

month = jul,

day = "15",

doi = "10.1002/ijc.32118",

language = "English (US)",

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Liu, Q, Wang, G, Li, Q, Jiang, W, Kim, JS, Wang, R, Zhu, S, Wang, X, Yan, L, Yi, Y, Zhang, L, Meng, Q, Li, C, Zhao, D, Qiao, Y, Li, Y, Gursel, DB, Chinnaiyan, AM, Chen, K & Cao, Q 2019, 'Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer', International Journal of Cancer, vol. 145, no. 2, pp. 415-426. https://doi.org/10.1002/ijc.32118

TY - JOUR

T1 - Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer

AU - Liu, Qipeng

AU - Wang, Guangyu

AU - Li, Qiaqia

AU - Jiang, Weihua

AU - Kim, Jung Sun

AU - Wang, Rui

AU - Zhu, Sen

AU - Wang, Xiaoju

AU - Yan, Lin

AU - Yi, Yang

AU - Zhang, Lili

AU - Meng, Qingshu

AU - Li, Chao

AU - Zhao, Dongyu

AU - Qiao, Yuanyuan

AU - Li, Yong

AU - Gursel, Demirkan B.

AU - Chinnaiyan, Arul M.

AU - Chen, Kaifu

AU - Cao, Qi

PY - 2019/7/15

Y1 - 2019/7/15

N2 - 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.

AB - 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.

KW - EED

KW - EZH2

KW - androgen receptor

KW - astemizole

KW - prostate cancer

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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