Krüppel-Like Factor 8 Induces Epithelial to Mesenchymal Transition and Epithelial Cell Invasion

Abstract

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. [Cancer Res 2007;67(15):7184-93]

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

“…KLF8 was initially identified as a transcription repressor of Krüppel-like C2H2 zinc-finger transcription factor family proteins (13). KLF8 influenced other tumor metastasis by EMT process (14) and was found to play an active role in renal cell carcinoma in which HIF-1 was highly expressed (15). However, the exact mechanism of KLF8 in hypoxia-induced EMT in gastric cancer remains to be elucidated.…”

Identification of Poly (ADP-ribose) Polymerase-1 (PARP-1) as a Novel Krüppel-like Factor 8-interacting and -regulating Protein

“…cellular processes including cell cycle progression (1-4), oncogenic transformation (5), epithelial-to-mesenchymal transition, migration, and invasion (6). The transcription of KLF8 is regulated by cell signaling molecules such as Src and PI3K downstream of focal adhesion kinase (1,7) and transcriptional activators such as Sp1 (2), KLF1, and KLF3 (8).…”

“…KLF8 binds directly to the cyclin D1 promoter and activates the transcription (1) by recruiting the p300 and p300/CBP-associated factor transcription co-activators (11). KLF8 also functions as a transcriptional repressor on the promoters of ␥-globin (10), KLF4 (3), and E-cadherin (6). Two nuclear localization signals on KLF8 were identified within the activation domain and the zinc finger domain, respectively (4,11).…”

“…HEK293T, T80, and MEF cells were maintained in DMEM supplemented with 10% fetal bovine serum (Mediatech) and 100 units/ml penicillin-streptomycin (Invitrogen). MCF10A cells were cultured as described previously (6). Transfections of the plasmid DNAs were performed using Lipofectamine2000 (Invitrogen) according to the manufacturer's instructions.…”

“…Chromatin Immunoprecipitation (ChIP) Assays-ChIP assays were performed essentially as we previously described (2,3,6,11,24), using the Millipore EZ-ChIP TM kit according to the manufacturer's protocol with minor modifications. pKH3 vector, pKH3-KLF8, or its ZF1,2mCs mutant (KLF8-mut) was transiently transfected into primary PARP-1 ϩ/ϩ or PARP-1 Ϫ/Ϫ MEF cells.…”