title: Requirement of PEA3 for transcriptional activation of FAK gene in tumor metastasis.
abstract: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase critically involved in cancer metastasis. We found an elevation of FAK expression in highly metastatic melanoma B16F10 cells compared with its less metastatic partner B16F1 cells. Down-regulation of the FAK expression by either small interfering RNA or dominant negative FAK (FAK Related Non-Kinase, FRNK) inhibited the B16F10 cell migration in vitro and invasiveness in vivo. The mechanism by which FAK activity is up-regulated in highly metastatic cells remains unclear. In this study, we reported for the first time that one of the Est family proteins, PEA3, is able to transactivate FAK expression through binding to the promoter region of FAK. We identified a PEA3-binding site between nucleotides -170 and +43 in the FAK promoter that was critical for the responsiveness to PEA3. A stronger affinity of PEA3 to this region contributed to the elevation of FAK expression in B16F10 cells. Both in vitro and in vivo knockdown of PEA3 gene successfully mimicked the cell migration and invasiveness as that induced by FAK down-regulation. The activation of the well-known upstream of PEA3, such as epidermal growth factor, JNK, and ERK can also induce FAK expression. Furthermore, in the metastatic human clinic tumor specimens from the patients with human primary oral squamous cell carcinoma, we observed a strong positive correlation among PEA3, FAK, and carcinoma metastasis. Taking together, we hypothesized that PEA3 might play an essential role in the activation of the FAK gene during tumor metastasis.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Shufeng
authors.initials: S
authors.lastname: Li
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Huang
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Qilai
authors.initials: Q
authors.lastname: Huang
authors.forename: Guoshun
authors.initials: G
authors.lastname: Pei
authors.forename: Lixiang
authors.initials: L
authors.lastname: Wang
authors.forename: Wenhui
authors.initials: W
authors.lastname: Jiang
authors.forename: Qingang
authors.initials: Q
authors.lastname: Hu
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.forename: Zi-Chun
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; C065788:transcription factor PEA3; D051416:Focal Adhesion Protein-Tyrosine Kinases