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J. Biol. Chem., Vol. 280, Issue 43, 36355-36363, October 28, 2005

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Modulation of Androgen Receptor Transactivation by FoxH1

A NEWLY IDENTIFIED ANDROGEN RECEPTOR COREPRESSOR^*

Guangchun Chen1, Masatoshi Nomura2, Hidetaka Morinaga, Eri Matsubara, Taijiro Okabe, Kiminobu Goto, Toshihiko Yanase, Hong Zheng¶, Jian Lu, and Hajime Nawata

From the Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan and Department of Pathophysiology and ^¶Laboratory Center of Pharmacology, Second Military Medical University, 800, Xiang Yin Road, Shanghai 200433, China

Androgen signaling plays key roles in the development and progression of prostate cancer, and numerous ongoing studies focus on the regulation of androgen receptor (AR) transactivity to develop novel therapies for the treatment of androgen-independent prostate cancer. FoxH1, a member of the Forkhead-box (FOX) gene family of transcription factors, takes part in mediating transforming growth factor-/activin signaling through its interaction with the Smad2·Smad4 complex. Using a series of experiments, we found that FoxH1 repressed both ligand-dependent and -independent transactivation of the AR on androgen-induced promoters. This action of FoxH1 was independent of its transactivation capacity and activin A but relieved by Smad2·Smad4. In addition, the repression of the AR by FoxH1 did not require deacetylase activity. A protein-protein interaction was identified between the AR and FoxH1 independently of dihydrotestosterone. Furthermore, a confocal microscopic analysis of LNCaP cells revealed that the interaction between the AR and FoxH1 occurred in the nucleus and that FoxH1 specifically blocked the foci formation of dihydrotestosterone-activated AR, which has been shown to be correlated with the AR transactivation potential. Taken together, our results indicate that FoxH1 functions as a new corepressor of the AR. Our observations not only strengthen the role of FoxH1 in AR-mediated transactivation but also suggest that therapeutic interventions based on AR-coregulator interactions could be designed to block both androgen-dependent and -independent growth of prostate cancer.

Received for publication, June 6, 2005 , and in revised form, August 11, 2005.

^* This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan. 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 Supported in part by a Sasakawa Medical Grant from the Japan-China Medical Association.

² To whom correspondence should be addressed. Tel.: 81-92-642-5280; Fax: 81-92-642-5297; E-mail: nomura{at}med.kyushu-u.ac.jp.

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