Abstract
Krüppel-like factors (KLFs) comprise a highly conserved family of zinc finger transcription factors, that are involved in a plethora of cellular processes, ranging from proliferation and apoptosis to differentiation, migration and pluripotency. During the last few years, evidence on their role and deregulation in different human cancers has been emerging. This review will discuss current knowledge on Krüppel-like transcription in the epithelial-mesenchymal transition (EMT), invasion and metastasis, with a focus on epithelial cancer biology and the extensive interface with pluripotency. Furthermore, as KLFs are able to mediate different outcomes, important influences of the cellular and microenvironmental context will be highlighted. Finally, we attempt to integrate diverse findings on KLF functions in EMT and stem cell biology to fit in the current model of cellular plasticity as a tool for successful metastatic dissemination.
Highlights
More variability exists within the N-terminal regions of Krüppel-like factors (KLFs), containing both activator and/or repressor domains that interact with specific coactivators and -repressors, providing unique functions to each family member
Direct binding sites for KLF4 have been detected in the promoter sequences of vimentin (VIM), VEGF-A (VEGFA), endothelin-1 (EDN1) and JNK-1 (MAPK8), next to E-cadherin (CDH1), N-cadherin (CDH2) and CTNNB1, indicating a central role for KLF4 within the epithelial-mesenchymal transition (EMT) program [35]
Epithelial cells can be driven to EMT under the influence of signaling events resulting from upstream extracellular cues (Fig 3)
Summary
EMT constitutes a transdifferentiation program whereby cells shift from an apical-basal to front-back polarity. Direct binding sites for KLF4 have been detected in the promoter sequences of vimentin (VIM), VEGF-A (VEGFA), endothelin-1 (EDN1) and JNK-1 (MAPK8), next to E-cadherin (CDH1), N-cadherin (CDH2) and CTNNB1, indicating a central role for KLF4 within the EMT program [35] These findings can at least partly explain the downregulation of KLF4 as reported for several epithelial cancer types and the inverse correlation of KLF4 expression with clinical outcome [32,36,37]. KLF5 activates CDH1 expression and downregulation of VIM in non-small cell lung cancer cells [40] Both KLF4 and KLF5 show competition for promoter binding sites with antagonizing effects regarding proliferation [41]. In HepG2 hepatic cancer cells, KLF17 was found to be under post-transcriptional regulation by miR-9, implying an oncogenic and pro-metastatic role for this miR through repression of KLF17 [61]
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