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Carcinogenesis Advance Access published online on January 6, 2009
Carcinogenesis, 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, Jing Ni1, Hong-Chiang Chang2, Chen-Yong Lin3, Mesut Muyan4 and Shuyuan Yeh1,*

1 Departments of Urology and Pathology
4 Departments of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14620, USA
2 Department of Urology, National Taiwan University, Taipei 10617, Taiwan
3 Department of Biochemistry and Molecular Biology, University of Maryland, Washington, DC

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

Human prostate cancer (PCa) and prostate epithelial cells predominantly express estrogen receptor β (ERβ), but not estrogen receptor {alpha} (ER{alpha}). ERβ might utilize various ER coregulators to mediate the E2 signaling pathway in PCa. Here we identified 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, GST pull-down, and co-immunoprecipitation methods proved that ERβ can interact with the C terminus of CCDC62/ERAP75 via the LBD. 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 (ERE)-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 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.

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


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