Abstract
Krüppel-like factor (KLF) family members share a three C2H2 zinc finger DNA binding domain, and are involved in cell proliferation and differentiation control in normal as in pathological situations. Studies over the past several years support a significant role for this family of transcription factors in carcinogenesis. KLFs can both activate and repress genes that participate in cell-cycle regulation. Among them, many up-regulated genes are inhibitors of proliferation, whereas genes that promote cell proliferation are repressed. However, several studies do present KLFs as positive regulator of cell proliferation. KLFs can be deregulated in multiple cancers either by loss of heterozygosity (LOH), somatic mutation or transcriptional silencing by promoter hypermethylation. Accordingly, KLF expression was shown to mediate growth inhibition when ectopically expressed in multiple cancer-derived cell lines through the inhibition of a number of key oncogenic signaling pathways, and to revert the tumorogenic phenotype in vivo. Taken together, these observations suggest that KLFs act as tumor suppressor. However, in some occasion, KLFs could act as tumor promoters, depending on “cellular context”. Thus, this review will discuss the roles and the functions of KLF family members in carcinogenesis, with a special focus on cancers from epithelial origin.
Highlights
Expression and Function of Krüppel-like factor (KLF) in Intestinal and Colon TumorsKLF4 or gut-enriched KLF (GKLF) is expressed extensively in the gastrointestinal (GI) tract from where it was first identified to maintain enterocyte differentiation and restrain cell proliferation
KLF4 or gut-enriched Krüppel-like factor (KLF) (GKLF) is expressed extensively in the gastrointestinal (GI) tract from where it was first identified to maintain enterocyte differentiation and restrain cell proliferation
In RKO cells, KLF4 stimulates intestinal alkaline phosphatase (IAP) gene expression, through a critical region including the IF-III cis element located within the proximal IAP promoter region [4]
Summary
KLF4 or gut-enriched KLF (GKLF) is expressed extensively in the gastrointestinal (GI) tract from where it was first identified to maintain enterocyte differentiation and restrain cell proliferation. KLF4 promoter activity is inhibited by Notch, which controls goblet cell differentiation in mouse GI tract [16], when Notch signaling suppresses KLF4 expression to support intestinal tumors and CRC progression [17]. Recent studies suggest that KLF4 functions as an activator or repressor of transcription depending on whether it interacts with co-activators such as p300 and CREB-binding protein or co-repressors such as histone deacetylase HDAC3 [25] Taken together, these studies clearly demonstrate that KLF4 plays an essential role in the regulation of cell growth in the colon. KLF5 transcription factor is described to play an oncogenic role in a human bladder cancer cell line, via increased G1 to S phase transition, up-regulation of cyclin D1 expression, phosphorylation of MAPK and Akt proteins, and inhibition of p27 and p15 expression [52]
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