Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis.
A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostate cancer (PCa), and loss of DAB2IP expression is frequently detected in metastatic PCa. However, the functional role of DAB2IP in PCa remains unknown. Here, we show that the loss of DAB2IP expression initiates epithelial-to-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in both human normal prostate epithelial and prostate carcinoma cells as well as in clinical prostate-cancer specimens. Conversely, restoring DAB2IP in metastatic PCa cells reversed EMT. In DAB2IP knockout mice, prostate epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human prostate xenograft-mouse model, we observed that knocking down endogenous DAB2IP in human carcinoma cells led to the development of multiple lymph node and distant organ metastases. Moreover, we showed that DAB2IP functions as a scaffold protein in regulating EMT by modulating nuclear beta-catenin/T-cell factor activity. These results show the mechanism of DAB2IP in EMT and suggest that assessment of DAB2IP may provide a prognostic biomarker and potential therapeutic target for PCa metastasis.
Xie
Daxing
D
Departmentsof Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Gore
Crystal
C
Liu
Jun
J
Pong
Rey-Chen
RC
Mason
Ralph
R
Hao
Guiyang
G
Long
Michael
M
Kabbani
Wareef
W
Yu
Luyang
L
Zhang
Haifeng
H
Chen
Hong
H
Sun
Xiankai
X
Boothman
David A
DA
Min
Wang
W
Hsieh
Jer-Tsong
JT
D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051820:TCF Transcription Factors / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D015820:Cadherins; C462952:DAB2IP protein, human; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D014746:Vimentin; D051176:beta Catenin; D020703:ras GTPase-Activating Proteins