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

Abstract

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 (ChIPchip). 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 lossof-function studies revealed that APP promotes the tumor growth of prostate cancer. The present study reveals a novel APP-mediated pathway responsible for the androgendependent 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]

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

“…Gain-of-function studies showed that APP overexpression leads to increased cellular proliferation (12,17,42). Lossof-function studies either by APP knockdown (14,16,17) or blockage of sAPP function by antibody application (15) demonstrated regression of carcinoma growth in vitro and in vivo. Such a functional relationship between APP expression and proliferation demonstrates the importance of APP in the pathogenesis of cancer.…”

“…The extracellular domain interacts with matrix proteins and heparan sulfate proteoglycans reflecting its role in migration, adhesion, and cell-matrix and cell-cell interactions (45)(46)(47)(48). Recently, it has been shown that APP is up-regulated in several cancer species, including pancreatic (15), colon (14), melanoma (49), and prostate cancer (17), as well as oral squamous cell carcinoma (15), and has growth-promoting features. Different kinds of stimuli can enhance APP expression.…”

“…Different kinds of stimuli can enhance APP expression. A recent study has revealed that APP transcription is androgen-inducible in prostate cancer (17). Under oncogenic and pro-inflammatory conditions (50), activation of Ras-MAPK can induce APP expression (51).…”

“…However, the predominant route of APP processing consists of successive cleavages by ␣-and ␥-secretases in non-neuronal cells (6,7). The cleavage of APP at Lys 16 -Leu 17 bond by ␣-secretase within the A␤ sequence liberates the sAPP␣ and the nonamyloidogenic C-terminal APP fragment (8 -10). APP is one of three members of a small gene family, which includes amyloid ␤ precursor-like protein 1 (APLP1) and amyloid ␤ precursor-like protein 2 (APLP2).…”

miR-148a is an androgen-responsive microRNA that promotes LNCaP prostate cell growth by repressing its target CAND1 expression

“…Our group and others have identified novel androgen target genes that regulate androgen-dependent tumor growth by performing chromatin immunoprecipitation coupled with tiling array (ChIP-chip) analyses. [8][9][10] Integrative transcriptome sequencing in prostate cancer cells could detect gene fusions, 11 including known prostate cancer-specific rearrangements TMPRSS2-ERG/ETV1. 12 Recently, miRNA profiling has been reported to be informative and predictive in some malignancies, including prostate cancer.…”