Abstract
Prostate cancer is a very common malignant disease and a leading cause of death for men in the Western world. Tumorigenesis and progression of prostate cancer involves multiple signaling pathways, including the Hippo pathway. Yes-associated protein (YAP) is the downstream transcriptional co-activator of the Hippo pathway, is overexpressed in prostate cancer, and plays a vital role in the tumorigenesis and progression of prostate cancer. However, the role of the YAP paralog and another downstream effector of the Hippo pathway, transcriptional co-activator with PDZ-binding motif (TAZ), in prostate cancer has not been fully elucidated. Here, we show that TAZ is a basal cell marker for the prostate epithelium. We found that overexpression of TAZ promotes the epithelial-mesenchymal transition (EMT), cell migration, and anchorage-independent growth in the RWPE1 prostate epithelial cells. Of note, knock down of TAZ in the DU145 prostate cancer cells inhibited cell migration and metastasis. We also found that SH3 domain binding protein 1 (SH3BP1), a RhoGAP protein that drives cell motility, is a direct target gene of TAZ in the prostate cancer cells, mediating TAZ function in enhancing cell migration. Moreover, the prostate cancer-related oncogenic E26 transformation-specific (ETS) transcription factors, ETV1, ETV4, and ETV5, were required for TAZ gene transcription in PC3 prostate cancer cells. MAPK inhibitor U0126 treatment decreased TAZ expression in RWPE1 cells, and ETV4 overexpression rescued TAZ expression in RWPE1 cells with U0126 treatment. Our results show a regulatory mechanism of TAZ transcription and suggest a significant role for TAZ in the progression of prostate cancer.
Highlights
Prostate cancer is a very common malignant disease and a leading cause of death for men in the Western world
We found that SH3 domain binding protein 1 (SH3BP1), a RhoGAP protein that drives cell motility, is a direct target gene of transcriptional coactivator with PDZ-binding motif (TAZ) in the prostate cancer cells, mediating TAZ function in enhancing cell migration
Our study is based on a relatively small number of patients, we did observe a tendency for TAZ expression to be correlated with a higher Gleason score, indicating that TAZ expression might be involved in the progression of prostate cancer and the indicator of more malignancy
Summary
We first examined TAZ expression in a commercial tissue array consisting of normal prostate tissue, hyperplasia tissue, and prostate cancer tissues. Compared with those injected with control DU145 cells, the mice inoculated with TAZ knockdown cells developed dramatically fewer lung metastases (Fig. 3D) These data indicate that TAZ promotes cell migration and metastasis in the prostate cancer cells. We tested the hypothesis that TAZ could promote cell migration and metastasis through up-regulation of SH3PB1 in prostate cancer cells Both Western blotting and qPCR analysis confirmed the decreased expression of SH3BP1 in the TAZ knockdown DU145 cells (Fig. 4A). The analysis of public ChIP-sequence data showed that multiple ETS transcription factors can bind to the promoter region of TAZ gene in the prostate cancer cells (supplemental Fig. 3A) [23, 24], prompting us to explore whether prostate cancer-related ETS TFs can regulate TAZ transcription. Our results indicate that prostate cancer-related ETS TFs (ETV1, ETV4, and ETV5) can promote TAZ expression in the prostate cancer
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