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Carcinogenesis Advance Access originally published online on January 6, 2009
Carcinogenesis 2009 30(5):841-850; doi:10.1093/carcin/bgn288
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

CCDC62/ERAP75 functions as a coactivator to enhance estrogen receptor beta-mediated transactivation and target gene expression in prostate cancer cells

Ming Chen1,2, Jing Ni1,2, Hong-Chiang Chang3, Chen-Yong Lin4, Mesut Muyan5 and Shuyuan Yeh1,2,*

1 Department of Urology
2 Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
3 Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan
4 Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD 21201, USA
5 Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA

* To whom correspondence should be addressed. Tel: +1 585 273 2750; Fax: +1 585 273 1068; Email: shuyuan_yeh{at}urmc.rochester.edu.

Human prostate cancer (PCa) and prostate epithelial cells predominantly express estrogen receptor (ER) β, but not ER{alpha}. ERβ might utilize various ER coregulators to mediate the E2-signaling pathway in PCa. Here, we identified coiled-coil domain containing 62 (CCDC62)/ERAP75 as a novel ER coactivator. CCDC62/ERAP75 is widely expressed in PCa cell lines and has low expression in MCF7 cells. Both in vitro and in vivo interaction assays using mammalian two-hybrid, glutathione S-transferase pull-down and coimmunoprecipitation methods proved that ERβ can interact with the C-terminus of CCDC62/ERAP75 via the ligand-binding domain. The first LXXLL motif within CCDC62/ERAP75 is required for the interaction between ERβ and CCDC62/ERAP75. Electrophoretic mobility shift assay showed that CCDC62/ERAP75 can be recruited by the estrogen response element–ER complex in the presence of ligand. Furthermore, a chromatin immunoprecipitation assay demonstrated the hormone-dependent recruitment of CCDC62/ERAP75 within the promoter of the estrogen-responsive gene cyclin D1. In addition, using silencing RNA (siRNA) against endogeneous CCDC62/ERAP75, we demonstrated that inhibition of endogenous CCDC62/ERAP75 results in the suppression of ERβ-mediated transactivation as well as target gene expression in LNCaP cells. More importantly, using the tet-on overexpression system, we showed that induced expression of CCDC62/ERAP75 can enhance the E2-regulated cyclin D1 expression and cell growth in LNCaP cells. Together, our results revealed the role of CCDC62/ERAP75 as a novel coactivator in PCa cells that can modulate ERβ transactivation and receptor function.

Abbreviations: aa, amino acid; AR, androgen receptor; CCDC62, coiled-coil domain containing 62; cDNA, complementary DNA; ChIP, chromatin immunoprecipitation assay; DBD, DNA-binding domain; Dox, doxycycline; EMSA, electrophoretic mobility shift assay; ER, estrogen receptor; ERE, estrogen response element; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GST, glutathione S-transferase; LBD, ligand-binding domain; NR, nuclear receptor; PCa, prostate cancer; PCR, polymerase chain reaction; siRNA, silencing RNA; SRC, steroid receptor coactivator; VDR, vitamin D receptor

Received July 20, 2008; revised December 15, 2008; accepted December 17, 2008.


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