Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth.
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.
Takayama
Ken-ichi
K
Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Tsutsumi
Shuichi
S
Suzuki
Takashi
T
Horie-Inoue
Kuniko
K
Ikeda
Kazuhiro
K
Kaneshiro
Kiyofumi
K
Fujimura
Tetsuya
T
Kumagai
Jinpei
J
Urano
Tomohiko
T
Sakaki
Yoshiyuki
Y
Shirahige
Katsuhiko
K
Sasano
Hironobu
H
Takahashi
Satoru
S
Kitamura
Tadaichi
T
Ouchi
Yasuyoshi
Y
Aburatani
Hiroyuki
H
Inoue
Satoshi
S
D000107:Acetylation; D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000728:Androgens / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058255:Protease Nexins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics*
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000728:Androgens; D014408:Biomarkers, Tumor; D006657:Histones; D058255:Protease Nexins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011956:Receptors, Cell Surface