Document Detail


Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex.
MedLine Citation:
PMID:  23038103     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Zhijian Duan; June X Zou; Ping Yang; Yuzhuo Wang; Alexander D Borowsky; Allen C Gao; Hong-Wu Chen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-04
Journal Detail:
Title:  The Prostate     Volume:  73     ISSN:  1097-0045     ISO Abbreviation:  Prostate     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-10     Revised Date:  2014-01-15    
Medline Journal Info:
Nlm Unique ID:  8101368     Medline TA:  Prostate     Country:  United States    
Other Details:
Languages:  eng     Pagination:  455-66     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphatases / genetics,  metabolism*
Androgens / metabolism*
Animals
Cell Line, Tumor
Chromatin / enzymology,  genetics
DNA-Binding Proteins / genetics,  metabolism*
Female
Gene Expression Regulation, Developmental / physiology
Histone-Lysine N-Methyltransferase / metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Multienzyme Complexes / metabolism*
Myeloid-Lymphoid Leukemia Protein / metabolism
Neoplasm Transplantation
Polycomb Repressive Complex 2 / genetics,  metabolism*
Pregnancy
Prostate* / embryology,  metabolism,  pathology
Prostatic Neoplasms / metabolism*,  pathology
RNA, Small Interfering / genetics
Sexual Maturation / physiology
Transplantation, Heterologous
Grant Support
ID/Acronym/Agency:
R01 CA140468/CA/NCI NIH HHS; R01CA134766/CA/NCI NIH HHS; R01DK060019/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Androgens; 0/Chromatin; 0/DNA-Binding Proteins; 0/MLL protein, human; 0/Multienzyme Complexes; 0/RNA, Small Interfering; 149025-06-9/Myeloid-Lymphoid Leukemia Protein; EC 2.1.1.-/histone methyltransferase; EC 2.1.1.43/EZH2 protein, human; EC 2.1.1.43/Ezh2 protein, mouse; EC 2.1.1.43/Histone-Lysine N-Methyltransferase; EC 2.1.1.43/Polycomb Repressive Complex 2; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.3/ATAD2 protein, human; EC 3.6.1.3/ATAD2 protein, mouse

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