Title
KLF8 and FAK cooperatively enrich the active MMP14 on the cell surface required for the metastatic progression of breast cancer
Abbreviated Journal Title
Oncogene
Keywords
KLF8; FAK; MMP14; beta-catenin/TCF1; metastasis; breast cancer; FOCAL ADHESION KINASE; KRUPPEL-LIKE FACTOR-8; E-CADHERIN; 1-MATRIX; METALLOPROTEINASE; MATRIX METALLOPROTEINASE-1; BETA-CATENIN/TCF4; COMPLEX; MESENCHYMAL TRANSITION; TUMOR-CELLS; TRANSCRIPTION; MT1-MMP; Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &; Heredity
Abstract
Kruppel-like factor 8 (KLF8) regulates critical gene transcription associated with cancer. The underlying mechanisms, however, remain largely unidentified. We have recently demonstrated that KLF8 expression enhances the activity but not expression of matrix metalloproteinase-2 (MMP2), the target substrate of MMP14. Here, we report a novel KLF8 to MMP14 signaling that promotes human breast cancer invasion and metastasis. Using cell lines for inducible expression and knockdown of KLF8, we demonstrate that KLF8 promotes MMP14 expression at the transcriptional level. Knocking down KLF8 expression inhibited the breast cancer cell invasion both in vitro and in vivo as well as the lung metastasis in mice, which could be rescued by ectopic expression of MMP14. Promoter reporter assays and oligonucleotide and chromatin immunoprecipitations determined that KLF8 activates the human MMP14 gene promoter by both directly acting on the promoter and indirectly via promoting the nuclear translocation of beta-catenin, the expression of T-cell factor-1 (TCF1) and subsequent activation of the promoter by the beta-catenin/TCF1 complex. Inhibition of focal adhesion kinase (FAK) using pharmacological inhibitor, RNA interference or knockout showed that the cell surface presentation of active MMP14 downstream of KLF8 depends on FAK expression and activity. Taken together, this work identified novel signaling mechanisms by which KLF8 and FAK work together to promote the extracellular activity of MMP14 critical for breast cancer metastasis.
Journal Title
Oncogene
Volume
33
Issue/Number
22
Publication Date
1-1-2014
Document Type
Article
Language
English
First Page
2909
Last Page
2917
WOS Identifier
ISSN
0950-9232
Recommended Citation
"KLF8 and FAK cooperatively enrich the active MMP14 on the cell surface required for the metastatic progression of breast cancer" (2014). Faculty Bibliography 2010s. 5724.
https://stars.library.ucf.edu/facultybib2010/5724
Comments
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