The Janus-faced roles of Krüppel-like factor 4 in oral squamous cell carcinoma cells

Oncotarget. 2015 Dec 29;6(42):44480-94. doi: 10.18632/oncotarget.6256.


Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that regulates many essential processes, including development and cell differentiation, proliferation, and apoptosis. Along with these roles in normal cells and tissues, KLF4 has important tumor suppressive and oncogenic functions in some malignancies. However, the roles of KLF4 in oral squamous cell carcinoma remain unclear. This study investigated the epigenetic alterations and possible roles of KLF4 in oral cancer carcinogenesis. Notably, KLF4 expression was significantly decreased in human oral cancer tissues compared with healthy controls, and KLF4 promoter hypermethylation contributed to the suppression of KLF4 expression. KLF4 expression was associated with tumor grade. Its expression was much lower in poorly differentiated oral cancers than in well-differentiated cancer cells. KLF4 exerted its antitumor activity in vitro and/or in vivo by inhibiting cell proliferation, cell cycle progression, cell colony formation and by inducing apoptosis. In addition, KLF4 over-expression promoted oral cancer cell migration and invasion in vitro. Knockdown of KLF4 promoted oral cancer cells growth and colony formation, and simultaneously inhibited cell migration and invasion. Mechanistic studies revealed that MMP-9 might contribute to KLF4-mediated cell migration and invasion. These results provide evidence that KLF4 might play Janus-faced roles in oral cancer carcinogenesis, acting both as a tumor suppressor and as an oncogene.

Keywords: KLF4; oncogene; oral squamous cell carcinoma; tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Case-Control Studies
  • Cell Cycle
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • DNA Methylation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Heterografts
  • Humans
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / pathology
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Promoter Regions, Genetic
  • RNA Interference
  • Signal Transduction
  • Squamous Cell Carcinoma of Head and Neck
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Oncogene Proteins
  • Tumor Suppressor Proteins
  • MMP9 protein, human
  • Matrix Metalloproteinase 9