Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion.
Tumor invasion and metastasis are the main causes of death from cancer. Epithelial to mesenchymal transition (EMT) is a determining step for a cancer cell to progress from a noninvasive to invasive state. Krüppel-like factor 8 (KLF8) plays a key role in oncogenic transformation and is highly overexpressed in several types of invasive human cancer, including breast cancer. To understand the role of KLF8 in regulating the progression of human breast cancer, we first established stable expression of KLF8 in an immortalized normal human breast epithelial cell line. We found that KLF8 strongly induced EMT and enhanced motility and invasiveness in the cells, by analyzing changes in cell morphology and epithelial and mesenchymal marker proteins, and using cell migration and Matrigel invasion assays. Chromatin immunoprecipitations (ChIP), oligonucleotide precipitations, and promoter-reporter assays showed that KLF8 directly bound and repressed the promoter of E-cadherin independent of E boxes in the promoter and Snail expression. Aberrant elevation of KLF8 expression is highly correlated with the decrease in E-cadherin expression in the invasive human breast cancer. Blocking KLF8 expression by RNA interference restored E-cadherin expression in the cancer cells and strongly inhibited the cell invasiveness. This work identifies KLF8 as a novel EMT-regulating transcription factor that opens a new avenue in EMT research and suggests an important role for KLF8 in human breast cancer invasion and metastasis.
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208, USA.
Xianhui
X
Wang
Mingzhe
M
Zheng
Gang
G
Liu
Weiya
W
Xia
Paula J
PJ
McKeown-Longo
Mien-Chie
MC
Hung
Jihe
J
Zhao
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008156:Luciferases / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015820:Cadherins; D004268:DNA-Binding Proteins; C507402:KLF8 protein, human; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D008156:Luciferases