1. KLF5 inhibition initiates epithelial-mesenchymal transition in non-transformed human squamous epithelial cells.
- Author
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Bhargava D, Rusakow D, Zheng W, Awad S, and Katz JP
- Subjects
- Humans, Cell Proliferation, Esophagus metabolism, Esophagus pathology, Esophageal Neoplasms metabolism, Esophageal Neoplasms pathology, Esophageal Neoplasms genetics, Signal Transduction, Epithelial-Mesenchymal Transition genetics, Kruppel-Like Transcription Factors metabolism, Kruppel-Like Transcription Factors genetics, Epithelial Cells metabolism, Epithelial Cells pathology, Cell Movement
- Abstract
The transcriptional regulator Krüppel-like factor 5 (KLF5) is highly expressed in squamous epithelial cells of the esophagus. Increased KLF5 activity induces tumorigenesis and promotes metastasis in several cancers, although this function appears to be context-dependent. Here, we demonstrate that acute KLF5 inhibition, both genetically and with the potent KLF5 inhibitor ML264, causes non-transformed human primary esophageal squamous epithelial cells to enter the epithelial to mesenchymal transition (EMT). Moreover, chronic KLF5 inhibition with ML264 leads to the development of cells with a mesenchymal phenotype characterized by the expression of mesenchymal markers and functionally by reduced cell growth and increased migration and cellular invasion. This EMT resulting from chronic KLF5 inhibition is not driven by β-Catenin or TGF-β signaling. Pharmacologically, ML264 inhibits KLF5 by promoting proteasomal-mediated degradation. Taken together, we demonstrate that reduced KLF5 activity reprograms epithelial cells towards a mesenchymal phenotype and enhances their migratory and invasive potential. These findings have potential implications not only for esophageal cancers but also for normal processes such as esophageal tissue repair following injury., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jonathan Katz reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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