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Cancer Genes and Genomics

Sterol Regulatory Element–Binding Protein-1c Represses the Transactivation of Androgen Receptor and Androgen-Dependent Growth of Prostatic Cells

¹Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea; ²Department of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul, Republic of Korea; and ³Department of Internal Medicine, Kyungpook University School of Medicine, Daegu, Republic of Korea

^* To whom correspondence should be addressed. E-mail: klee{at}chonnam.ac.kr.

	Abstract

Sterol regulatory element-binding protein-1c (SREBP-1c) is a basic helix-loop-helix transcription factor that plays an important role in lipid homeostasis. Here, we show that SREBP-1c regulates androgen receptor (AR) transactivation through direct interaction with AR and represses androgen-dependent growth of prostatic cells. Transient transfection studies show that SREBP-1c specifically inhibits the transactivation of AR. Chromatin immunoprecipitation assays reveal that SREBP-1c is recruited with AR onto the endogenous AR target promoter. Moreover, adenovirus-mediated overexpression of SREBP-1c decreases the mRNA level of the prostate-specific antigen gene, an endogenous target gene of AR, supporting SREBP-1c modulation of AR transactivation. In vivo and in vitro protein interaction assays show that SREBP-1c directly interacts with AR through the activation function-1 domain of AR. In addition, transfection studies and glutathione S-transferase pull-down competition experiments reveal that the SREBP-1c–mediated repression of AR transactivation is accomplished through competition with certain AR coactivators for AR interaction. The SREBP-1c–mediated inhibition of AR transactivation also involves the recruitment of histone deacetylase 1. Finally, adenovirus-mediated overexpression of SREBP-1c inhibits androgen-induced proliferation of prostatic cells in vitro and in vivo, and small interfering RNA–mediated down-regulation of SREBP-1 enhances androgen-induced proliferation of prostatic cells as well as the transactivation of AR. Taken together, these results suggest that SREBP-1c acts as an AR corepressor and may play an important role in the regulation of AR-dependent prostatic cell growth. (Mol Cancer Res 2008;6(2):OF1–11)

Key Words: androgen receptor, prostate cancer, corepressor, SREBP-1c, PSA