TM4SF1, A Novel Primary Androgen Receptor Target Gene Over-Expressed in Human Prostate Cancer and Involved in Cell Migration

BACKGROUND. The Androgen Receptor (AR) plays a key role in controlling prostate gland homeostasis and contributes to prostate carcinogenesis. The identification of its target genes should provide new candidates that may be implicated in cancer initiation and progression. METHODS. Transcriptomic experiments and chromatin immunoprecipitation were combined to identify direct androgen regulated genes. Real-time quantitative PCR (RT-qPCR) analyseswere performed tomeasure TM4SF1 mRNA levels in prostate cancer and benign prostatic hyperplasia (BPH) specimens. Immunohistochemicalmethodswere used to compare TM4SF1 protein expressionprofiles in the same cohort. AtargetedsiRNAs knockdown strategywas used, prior towound healing assays, to analyze the role of TM4SF1 in cell migration in vitro. RESULTS. We demonstrate for the first time that TM4SF1 is a direct target gene of the AR, a transcription factor of the steroidnuclear receptor family. A functional androgen response element was identified in the promoter region of the gene. In addition, TM4SF1 mRNA expression was higher in cancer samples compared to BPH tissues. The TM4SF1 protein mediates cell motility of prostate cancer cells where it is predominantly localized in the cytoplasm, in contrast to its apical membrane localization in normal prostate epithelial cells. CONCLUSIONS. Our results reveal a novel function for TM4SF1 in AR signaling. The TM4SF1 mRNA expression is higher in prostate cancer tissues as compared to BPH samples. Inhibition of cell migration after targeted knockdown of TM4SF1 protein expression suggests its contribution to prostate cancer cell metastasis. Prostate 71: 1239-1250, 2011. (C) 2011 Wiley-Liss, Inc.