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Papers In Press, published online ahead of print October 22, 2001
J. Biol. Chem, 10.1074/jbc.M108312200
Submitted on August 28, 2001
Revised on October 18, 2001
Accepted on October 19, 2001

A dominant-negative mutant of androgen receptor coregulator ARA54 inhibits androgen receptor-mediated prostate cancer growth

Hiroshi Miyamoto, Mujib Rahman, Hiroshi Takatera, Hong-Yo Kang, Shuyuan Yeh, Hong-Chiang Chang, Kazuo Nishimura, Naohiro Fujimoto, and Chawnshang Chang

Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642

Corresponding Author: chang{at}urmc.rochester.edu

The ligand-bound androgen receptor (AR) regulates target genes via a mechanism involving coregulators, such as ARA54. We investigated whether interruption of the AR coregulator function could lead to down-regulation of AR activity. Using in vitro mutagenesis and a yeast two-hybrid screening assay, we have isolated a mutant ARA54 (mt-ARA54) carrying a point mutation at amino acid 472 changing a glutamic acid to lysine, which acts as a dominant-negative inhibitor of AR transactivation. In transient transfection assays of prostate cancer cell lines, the mt-ARA54 suppressed endogenous mutated AR- and exogenous wild-type AR-mediated transactivation in LNCaP and PC-3 cells, respectively. In DU145 cells, the mt-ARA54 suppressed exogenous ARA54-, but not other coregulator-, such as ARA55- or SRC-1-, enhanced AR transactivation. In the LNCaP cells stably transfected with the plasmids encoding the mt-ARA54 under the doxycycline inducible system, overexpression of the mt-ARA54 inhibited cell growth and endogenous expression of prostate-specific antigen. Mammalian two-hybrid assays further demonstrated that the mt-ARA54 can disrupt the interaction between wild-type ARA54 molecules, suggesting ARA54 dimerization or oligomerization may play an essential role in the enhancement of AR transactivation. Together, our results demonstrate that a dominant-negative AR coregulator can suppress AR transactivation and cell proliferation in prostate cancer cells. Further studies may provide a new therapeutic approach for blocking AR-mediated prostate cancer growth.


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