科研之友
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摘要
p63 is a member of the p53 transcription factor family and a linchpin of epithelial development and homeostasis. p63 drives the expression of many target genes involved in cell survival, adhesion, migration and cancer. In this study, we identify C-terminal tensin-like (CTEN) molecule as a downstream target of Delta Np63 alpha, the predominant p63 isoform expressed in epithelium. CTEN belongs to the tensin family and is mainly localized to focal adhesions, which mediate many biological events such as cell adhesion, migration, proliferation and gene expression. Our study demonstrate that Delta Np63 and CTEN are both highly expressed in normal prostate epithelial cells and are down-regulated in prostate cancer. In addition, reduced expression of CTEN and Delta Np63 is correlated with prostate cancer progression from primary tumors to metastatic lesions. Silencing of Delta Np63 leads to decreased mRNA and protein levels of CTEN Delta Np63 alpha induces transcriptional activity of the CTEN promoter and a 140-bp fragment upstream of the transcription initiation site is the minimal promoter region required for activation. A putative binding site for p63 is located between -61 and -36 within the CTEN promoter and mutations of the critical nucleotides in this region abolish Delta Np63 alpha-induced promoter activity. The direct interaction of Delta Np63 alpha-mediated with the CTEN promoter was demonstrated using a chromatin immunoprecipitation (ChIP) assay. Moreover, impaired cell adhesion caused by Delta Np63 alpha depletion is rescued by over-expression of CTEN, suggesting that CTEN is a downstream effector of Delta Np63 alpha-mediated cell adhesion. In summary, our findings demonstrate that Delta Np63 alpha functions as a trans-activation factor of CTEN promoter and regulates cell adhesion through modulating CTEN. Our study further contributes to the potential regulatory mechanisms of CTEN in prostate cancer progression.
- 出版日期2016-1-19
