title: ΔNp63α Transcriptionally Regulates the Expression of CTEN That Is Associated with Prostate Cell Adhesion.
abstract: 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 ΔNp63α, 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 ΔNp63 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 ΔNp63 is correlated with prostate cancer progression from primary tumors to metastatic lesions. Silencing of ΔNp63 leads to decreased mRNA and protein levels of CTEN. ΔNp63α 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 ΔNp63α-induced promoter activity. The direct interaction of ΔNp63α with the CTEN promoter was demonstrated using a chromatin immunoprecipitation (ChIP) assay. Moreover, impaired cell adhesion caused by ΔNp63α depletion is rescued by over-expression of CTEN, suggesting that CTEN is a downstream effector of ΔNp63α-mediated cell adhesion. In summary, our findings demonstrate that ΔNp63α 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.
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuan
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Wu
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, California, United States of America.
authors.forename: Su Hao
authors.initials: SH
authors.lastname: Lo
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Liao
mesh_terms: D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000070876:Tensins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008840:Microfilament Proteins; D012333:RNA, Messenger; C000603371:TNS4 protein, human; C115051:TP63 protein, human; D000070876:Tensins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins