Identification of epithelial stromal interaction 1 as a novel effector downstream of Kruppel-like factor 8 in breast cancer invasion and metastasis

    Authors

    Oncogene

    Comments

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    Abbreviated Journal Title

    J. Disp. Technol.

    Keywords

    KLF8; EPSTI1; VCP; NF-kappa B; invasion and metastasis; breast cancer; FOCAL ADHESION KINASE; CELL-CYCLE PROGRESSION; HUMAN SOMATIC-CELLS; ONCOGENIC TRANSFORMATION; MESENCHYMAL TRANSITION; KLF8 TRANSCRIPTION; ACTIVATION; MICROENVIRONMENT; SUMOYLATION; VCP/P97; Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &; Heredity

    Abstract

    Kruppel-like factor 8 (KLF8) is a transcriptional factor critical for metastatic progression of breast cancer. Epithelial stromal interaction 1 (EPSTI1), a recently identified stromal fibroblast-induced gene in non-invasive breast cancer cells is highly overexpressed in invasive breast carcinomas. The function and regulation of EPSTI1, however, remain largely unknown. In this paper, we report a novel KLF8 to EPSTI1 signaling pathway in breast cancer. Using various expression analyses, we revealed a high co-overexpression of KLF8 and EPSTI1 in invasive human breast cancer cells and patient tumors. Ectopic overexpression of KLF8 in the non-invasive MCF-10A cells induced the EPSTI1 expression, whereas KLF8 knockdown from the invasive, MDA-MB-231 cells decreased the EPSTI1 expression. Promoter activation and binding analyses indicated that KLF8 promoted the EPSTI1 expression by directly acting on the EPSTI1 gene promoter. EPSTI1 knockdown dramatically reduced the KLF8-promoted MCF-10A cell invasion, and ectopic expression of EPSTI1 in the non-invasive MCF-7 cells is sufficient to induce the cell invasion. Experiments using nude mice demonstrated that the ectopic EPSTI1 granted the MCF-7 cells capability of both invasive growth in the breasts and metastasis to the lungs. Using co-immunoprecipitation coupled with mass spectrometry, we discovered that EPSTI1 interacts with the valosin-containing protein (VCP), resulting in the degradation of I kappa B alpha and subsequent activation of NF-kappa B in the nucleus. These findings suggest a novel KLF8 to EPSTI1 to VCP to NF-kappa B signaling mechanism potentially critical for breast cancer invasion and metastasis.

    Subjects

    T. Li; H. Lu; C. Shen; S. K. Lahiri; M. S. Wason; D. Mukherjee; L. Yu;J. Zhao

    Volume

    33

    Issue/Number

    39

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    4746

    Last Page

    4755

    WOS Identifier

    WOS:000343239500005

    ISSN

    0950-9232

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