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Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex

Authors

  • Zhijian Duan,

    1. Cancer Center/Basic Sciences, University of California at Davis, Sacramento, California
    2. Graduate Program of Pharmacology and Toxicology, University of California at Davis, Sacramento, California
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  • June X. Zou,

    1. Department of Internal Medicine, University of California at Davis, Sacramento, California
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  • Ping Yang,

    1. Cancer Center/Basic Sciences, University of California at Davis, Sacramento, California
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  • Yuzhuo Wang,

    1. Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada
    2. The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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  • Alexander D. Borowsky,

    1. Department of Pathology, University of California at Davis, Sacramento, California
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  • Allen C. Gao,

    1. Department of Urology, University of California at Davis, Sacramento, California
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  • Hong-Wu Chen

    Corresponding author
    1. Cancer Center/Basic Sciences, University of California at Davis, Sacramento, California
    2. Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, California
    • UC Davis Cancer Center, UCDMC Research III, Rm 1400B, 4645 2nd Ave, Sacramento, CA 95817.
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Abstract

BACKGROUND

Chromatin regulators ANCCA and EZH2 are overexpressed in prostate cancer and play crucial roles in androgen-stimulated and castration-refractory prostate tumor growth and survival. However, how their expression is regulated in the tumors and whether they play a role in prostate development remains unclear.

METHODS

Prostate tissue from different developmental stages of mouse and human were examined by IHC, qRT-PCR and Western for expression of ANCCA, EZH2, and Ki-67. Animals were castrated and T-implanted for the expression response in normal prostate and tumors. siRNA knockdown and ChIP were performed for the mechanism of ANCCA regulation of EZH2.

RESULTS

In contrast to their very low level expression in adult prostate, ANCCA and EZH2 are strongly expressed in the epithelium and mesenchyme of mouse and human UGS. Their expression becomes more restricted to epithelial cells during later development and displays a second peak during puberty, which correlates with the proliferative status of the epithelium. Importantly, their expression in normal prostate and tumors is strongly suppressed by castration and markedly induced by testosterone replacement. While androgen suppresses EZH2 in CRPC cells, in LNCaP cells, physiological concentrations of androgen stimulate expression of PRC2 genes (EZH2, SUZ12, and EED), which is mediated by androgen-induced ANCCA and involves E2F and histone H3K4me3 methylase MLL1 complex.

CONCLUSION

EZH2 and ANCCA are androgen regulated and strongly expressed in early prostate morphogenesis and during puberty, suggesting their important role in prostate development. Regulation of EZH2 by ANCCA emphasizes bromodomain protein ANCCA as a potential therapeutic target against prostate cancer. Prostate 73: 455–466, 2013. © 2012 Wiley Periodicals, Inc.

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