Title

KLF8 and FAK cooperatively enrich the active MMP14 on the cell surface required for the metastatic progression of breast cancer

Authors

Authors

H. Lu; L. Hu; L. Yu; X. Wang; A. M. Urvalek; T. Li; C. Shen; D. Mukherjee; S. K. Lahiri; M. S. Wason;J. Zhao

Comments

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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

WOS:000337231800010

ISSN

0950-9232

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