ErbB3 binding protein 1 represses metastasis-promoting gene anterior gradient protein 2 in prostate cancer.
Dysregulation of the developmental gene anterior gradient protein 2 (AGR2) has been associated with a metastatic phenotype, but its mechanism of action and control in prostate cancers is unknown. In this study, we show that overexpression of AGR2 promotes the motility and invasiveness of nonmetastatic LNCaP tumor cells, whereas silencing of AGR2 in the metastatic derivative C4-2B blocks invasive behavior. ErbB3 binding protein 1 (EBP1), a putative repressor of AGR2, is attenuated in prostate cancer. We show that the anti-invasive effect of EBP1 occurs, at least in part, through its ability to inhibit AGR2 expression. Mechanistic investigations indicate that EBP1 downregulates Foxa1- and Foxa2-stimulated AGR2 transcription and decreases metastatic behavior. In contrast, EBP1 ablation upregulates AGR2 via Foxa1- and Foxa2-stimulated AGR2 promoter activity and increases metastatic behavior. In both prostate cell lines and primary tumors, we documented an inverse correlation between EBP1 and AGR2 levels. Collectively, our results reveal an EBP1-Foxa-AGR2 signaling circuit with functional significance in metastatic prostate cancer.
Zhang
Yuexing
Y
Greenebaum Cancer Center and Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. Yzhan001@umaryland.edu
Ali
Tehmina Z
TZ
Zhou
Hua
H
D'Souza
David R
DR
Lu
Yan
Y
Jaffe
Jonathan
J
Liu
Zhenqiu
Z
Passaniti
Antonino
A
Hamburger
Anne W
AW
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D009088:Mucoproteins; D009361:Neoplasm Invasiveness / Q000235:genetics*; D015513:Oncogene Proteins; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D046888:Tissue Array Analysis; D014162:Transfection
C502296:AGR2 protein, human; D048868:Adaptor Proteins, Signal Transducing; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D009088:Mucoproteins; D015513:Oncogene Proteins; C101633:PA2G4 protein, human; D011506:Proteins; D016601:RNA-Binding Proteins; D051542:Hepatocyte Nuclear Factor 3-beta