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J. Biol. Chem., Vol. 282, Issue 31, 22651-22661, August 3, 2007

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Glyceraldehyde-3-phosphate Dehydrogenase Enhances Transcriptional Activity of Androgen Receptor in Prostate Cancer Cells^*

Naoki Harada, Ryoko Yasunaga, Yasuki Higashimura, Ryoichi Yamaji¹, Katsumi Fujimoto, Joel Moss^¶, Hiroshi Inui, and Yoshihisa Nakano

From the Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan, the Departments of Dental and Medical Biochemistry, Graduate School of Biochemical Sciences, Hiroshima University, Hiroshima 7348553, Japan, and the ^¶Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

Androgen receptor (AR) functions as a transcriptional factor for genes involved in proliferation and differentiation of normal and cancerous prostate cells. Coactivators that bind to AR are required for maximal androgen action. Here we report that increasing the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a prostate cancer cell line by as little as 1.8-fold enhances transcriptional activity of AR (but not the transcriptional activity of glucocorticoid receptor or estrogen receptor ) in a ligand-dependent manner and results in an increased expression of prostate-specific antigen. Small interference RNA-mediated knockdown of GAPDH significantly attenuated ligand-activated AR transactivation. Immunoprecipitation analysis revealed the presence of an endogenous protein complex containing GAPDH and AR in both the cytoplasm and nucleus. Addition of a nuclear localization signal (NLS) to GAPDH (GAPDH-NLS) completely abolished the ability of GAPDH to transactivate AR. Neither wild-type GAPDH nor GAPDH-NLS enhanced transcriptional activity of mutant AR (ARC-Nuc) that is a constitutively active form of AR in the nucleus, even though GAPDH-NLS formed a complex with wild-type AR or ARC-Nuc. AR transactivation was enhanced by a mutant GAPDH lacking dehydrogenase activity. GAPDH enhanced the transcriptional activity of AR(T875A) activated by an antagonist such as hydroxyflutamide or cyproterone acetate. These results indicate that GAPDH functions as a coactivator with high selectivity for AR and enhances AR transactivation independent of its glycolytic activity. Further, these data suggest that formation of a GAPDH·AR complex in the cytoplasm rather than nucleus is essential for GAPDH to enhance AR transactivation.

Received for publication, November 20, 2006 , and in revised form, April 25, 2007.

^* This work was supported by Grant-in-Aid (18580127) for scientific research (to R. Y.) from the Japan Society for the Promotion of Science, a Special Research Grant (to R. Y.) from Osaka Prefecture University and Sasagawa Scientific Research Grant (18–141) (to N. H.) from the Japan Science Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Tel./Fax: 81-72-254-9454; E-mail: yamaji{at}biochem.osakafu-u.ac.jp.

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