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Amyloid Precursor Protein Is a Primary Androgen Target Gene That Promotes Prostate Cancer Growth

Departments of ¹ Geriatric Medicine and ² Anti-Aging Medicine, Graduate School of Medicine, University of Tokyo; ³ Department of Urology, University of Tokyo Hospital, Bunkyo-ku; ⁴ Research Center for Genomic Medicine, Saitama Medical University, Hidaka; ⁵ Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Meguro-ku; ⁶ Department of Pathology, Tohoku University School of Medicine, Sendai; ⁷ Genomic Sciences Center, Yokohama Institute, RIKEN; ⁸ Division for Gene Research, Center for Biological Resources and Informatics, Tokyo Institute of Technology, Yokohama; and ⁹ CREST, Japan Science and Technology Agency, Kawaguchi, Japan

Requests for reprints: Satoshi Inoue, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-9125; Fax: 81-3-5800-9126; E-mail: INOUE-GER{at}h.u-tokyo.ac.jp.

Key Words: androgen receptor • prostate cancer • amyloid precursor protein • chromatin immunoprecipitation

Androgen receptor (AR) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently. Here, we identify amyloid precursor protein (APP) as a primary androgen target through chromatin immunoprecipitation (ChIP) combined with genome tiling array analysis (ChIP-chip). ChIP-treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies. Ligand-dependent AR binding was further enriched by PCR subtraction. Using chromosome 21/22 arrays, we identified APP as one of the androgen-regulated genes with adjacent functional AR binding sites. APP expression is androgen-inducible in LNCaP cells and APP immunoreactivity was correlated with poor prognosis in patients with prostate cancer. Gain-of-function and loss-of-function studies revealed that APP promotes the tumor growth of prostate cancer. The present study reveals a novel APP-mediated pathway responsible for the androgen-dependent growth of prostate cancer. Our findings will indicate that APP could be a potential molecular target for the diagnosis and treatment of prostate cancer. [Cancer Res 2009;69(1):137–42]

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