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
N1 - Funding Information:
Key words: EZH2, EED, androgen receptor, astemizole, prostate cancer Additional Supporting Information may be found in the online version of this article. Q.L., G.W. and Q.L. contributed equally to this work Yong Li’s current address is: Department of Anatomy and Biology, School of Medicine, Indiana University, Bloomington, IN Grant sponsor: NIH/NHLBI; Grant numbers: HL099997, HL100397; Grant sponsor: NIH/NCI; Grant number: R01CA208257; Grant sponsor: American Cancer Society; Grant number: TBE-128382; Grant sponsor: U.S. Department of Defense; Grant numbers: W81XWH-15-1-0639, W81XWH-17-1-0357; Grant sponsor: Prostate Cancer Foundation; Grant number: 13YOUN007; Grant sponsor: Houston Methodist Research Institute; Grant sponsor: Northwestern University DOI: 10.1002/ijc.32118 History: Received 12 Jun 2018; Accepted 19 Dec 2018; Online 10 Jan 2019 Correspondence to: Kaifu Chen, Ph.D. 6670 Bertner Ave, R10-217, Houston Methodist Research Institute, Houston, TX 77030, E-mail: [email protected]; Tel.: (+1) 713-363-7205; or Qi Cao, Ph.D. 303 E. Chicago Ave, Tarry 16-707, Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, Tel.: +1-312-503-5990, E-mail: [email protected]
Funding Information:
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
Publisher Copyright:
© 2019 UICC
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
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
KW - Humans
KW - Male
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Signal Transduction/drug effects
KW - Xenograft Model Antitumor Assays
KW - Enhancer of Zeste Homolog 2 Protein/metabolism
KW - Animals
KW - Sequence Analysis, RNA
KW - Receptors, Androgen/genetics
KW - Polycomb Repressive Complex 2/metabolism
KW - Astemizole/administration & dosage
KW - Cell Line, Tumor
KW - Prostatic Neoplasms/drug therapy
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85061402844&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061402844&partnerID=8YFLogxK
U2 - 10.1002/ijc.32118
DO - 10.1002/ijc.32118
M3 - Article
C2 - 30628724
AN - SCOPUS:85061402844
SN - 0020-7136
VL - 145
SP - 415
EP - 426
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 2
ER -