Modulation of the Expression and Transactivation of Androgen Receptor by the Basic Helix-Loop-Helix Transcription Factor Pod-1 through Recruitment of Histone Deacetylase 1

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2005-09, Vol.19 (9), p.2245-2257
• Main Authors: Hong, Cheol Yi, Gong, Eun-Yeung, Kim, Kabsun, Suh, Ji Ho, Ko, Hyun-Mi, Lee, Hyun Joo, Choi, Hueng-Sik, Lee, Keesook
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cells, Cultured; Chromatin Immunoprecipitation; Down-Regulation; E-Box Elements; Gene Expression Regulation; Histone Deacetylase 1; Histone Deacetylases - metabolism; Homeodomain Proteins - genetics; Humans; Male; Mice; Promoter Regions, Genetic; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Sequence Deletion; Testis - growth & development; Transcription Factors - genetics; Transcriptional Activation; Two-Hybrid System Techniques
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2004-0400

Androgen receptor (AR) is important in male sexual differentiation and testicular function. Here, we demonstrate the regulation of AR expression and its transactivation by the basic helix-loop-helix (bHLH) transcription factor Pod-1, the expression of which in postnatal testis reciprocally coincides with the expression of AR. Pod-1 represses the promoter activity of AR, possibly through its E-box. An AR promoter region of 169 bp, which harbors one canonical E-box, is sufficient for the Pod-1-repression and bound by purified Pod-1 proteins. Pod-1 also suppresses the transactivation of AR. Transient transfection analyses of mammalian cells show that Pod-1 represses AR transactivation in a dose-dependent manner. Furthermore, yeast two-hybrid, glutathione-S-transferase-pull-down, and coimmunoprecipitation analyses reveal that Pod-1 directly associates with AR through its N-terminal region and through the DNA binding-hinge domain of AR. Interestingly, Pod-1 recruits histone deacetylase (HDAC)-1 to inhibit both promoter activity and transactivation of AR. Overexpression of HDAC1 further inhibits the Pod-1-mediated repressions and Pod-1 directly interacts with HDAC1. Furthermore, chromatin immunoprecipitation assay reveals that HDAC1 is recruited with Pod-1 to the endogenous AR promoter and the androgen-regulated Pem promoter. Taken together, these results suggest that Pod-1, which controls AR transcription and function, may play an important role in the development and function of the testis.