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Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity

  • Le Minh, Giang1
  • Esquea, Emily M.1
  • Dhameliya, Tejsi T.1
  • Merzy, Jessica1
  • Lee, Mi-Hye2
  • Ball, Lauren E.2
  • Reginato, Mauricio J.1, 3
  • 1 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA , (United States)
  • 2 Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC , (United States)
  • 3 Translational and Cellular Oncology Program, Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA , (United States)
Published Article
Frontiers in Oncology
Frontiers Media SA
Publication Date
Apr 19, 2023
DOI: 10.3389/fonc.2023.1141834
  • Oncology
  • Original Research


Introduction Breast tumor development is regulated by a sub-population of breast cancer cells, termed cancer stem-like cells (CSC), which are capable of self-renewing and differentiating, and are involved in promoting breast cancer invasion, metastasis, drug resistance and relapse. CSCs are highly adaptable, capable of reprogramming their own metabolism and signaling activity in response to stimuli within the tumor microenvironment. Recently, the nutrient sensor O-GlcNAc transferase (OGT) and O-GlcNAcylation was shown to be enriched in CSC populations, where it promotes the stemness and tumorigenesis of breast cancer cells in vitro and in vivo. This enrichment was associated with upregulation of the transcription factor Kruppel-like-factor 8 (KLF8) suggesting a potential role of KLF8 in regulating CSCs properties. Methods Triple-negative breast cancer cells were genetically modified to generate KLF8 overexpressing or KLF8 knock-down cells. Cancer cells, control or with altered KLF8 expression were analyzed to assess mammosphere formation efficiency, CSCs frequency and expression of CSCs factors. Tumor growth in vivo of control or KLF8 knock-down cells was assessed by fat-pad injection of these cell in immunocompromised mice. Results Here, we show that KLF8 is required and sufficient for regulating CSC phenotypes and regulating transcription factors SOX2, NANOG, OCT4 and c-MYC. KLF8 levels are associated with chemoresistance in triple negative breast cancer patients and overexpression in breast cancer cells increased paclitaxel resistance. KLF8 and OGT co-regulate each other to form a feed-forward loop to promote CSCs phenotype and mammosphere formation of breast cancer cells. Discussion These results suggest a critical role of KLF8 and OGT in promoting CSCs and cancer progression, that may serve as potential targets for developing strategy to target CSCs specifically.

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