Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer

Ohnishi, Shunsuke; Ohnami, Sumiko; Laub, Friedrich; Aoki, Kazunori; Suzuki, Koichi; Kanai, Yae; Haga, Kazunori; Asaka, Masahiro; Ramirez, Francesco; Yoshida, Teruhiko

doi:10.1016/s0006-291x(03)01356-1

Cited by 165 publications

(134 citation statements)

References 23 publications

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“…Collectively, these findings indicate that KLF4 is a potential tumor suppressor in colorectal cancer. A similar down-regulation and growth suppressive effect of KLF4 has also been described in bladder cancer [25].…”

Section: Klf4 and 5 Exhibit Contrasting Effects On Cellular Proliferasupporting

confidence: 68%

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

et al. 2005

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Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with diverse regulatory functions in cell growth, proliferation, differentiation, and embryogenesis. KLF4 and KLF5 are two closely related members of the KLF family that have a similar tissue distribution in embryos and adults. However, the two KLFs often exhibit opposite effects on regulation of gene transcription, despite binding to similar, if not identical, cis-acting DNA sequences. In addition, KLF4 and 5 exert contrasting effects on cell proliferation in many instances; while KLF4 is an inhibitor of cell growth, KLF5 stimulates proliferation. Here we review the biological properties and biochemical mechanisms of action of the two KLFs in the context of growth regulation.

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Section: Klf4 and 5 Exhibit Contrasting Effects On Cellular Proliferasupporting

confidence: 68%

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

et al. 2005

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“…Consistent with this notion, KLF4 is downregulated in many human cancers, including esophageal, gastric, colorectal, bladder and prostate cancers, whereas it is overexpressed in primary breast ductal carcinomas and oral squamous cell carcinomas (Foster et al, 2000;Wang et al, 2002;Ohnishi et al, 2003;Luo et al, 2004).…”

Section: Introductionmentioning

confidence: 88%

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

et al. 2009

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Kruppel-like factor 4 (KLF4) is a transcription factor that participates in both tumor suppression and oncogenesis. To determine the association of KLF4 with tumorigenesis, we integrated data assembled in the Oncomine database and discovered a decrease in KLF4 gene transcripts in breast cancers. Further analysis of the database also showed a correlation between KLF4 expression and estrogen receptor-a (ERa) positivity. Knockdown of KLF4 in MCF-7 cells elevated the growth rate of these cells in the presence of estrogen. Therefore, we examined the interaction between KLF4 and ERa, and found that KLF4 bound to the DNA-binding region of ERa. KLF4 thus inhibits the binding of ERa to estrogen response elements in promoter regions, resulting in a reduction in ERa target gene transcription. Earlier studies have reported that KLF4 is transcriptionally activated by p53 following DNA damage. We also showed that activation of p53 decreased the transcriptional activity of ERa by elevating KLF4 expression. Our studies discovered a novel molecular network between p53, KLF4 and ERa. As both p53 and ERa are involved in cell growth and apoptosis, these results may explain why KLF4 possesses both tumor suppressive and oncogenic functions in breast cancers.

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confidence: 90%

“…In mice, ectopic expression of Klf4 accelerates terminal differentiation, leading to premature skin-barrier acquisition 7 , whereas Klf4 deficiency prevents the terminal differentiation of colonic goblet cells 8 and the skin epithelium 9 , which leads to neonatal death 9 . These observations establish KLF4 as a stress-and differentiation-associated inhibitor of proliferation 10 , raising the possibility that KLF4 may have tumour-suppressive functions 8,11,12 .Indeed, KLF4 expression is frequently lost in various human cancer types 11,[13][14][15][16][17][18][19] . Recently, KLF4 has been shown to undergo promoter methylation and loss of heterozygosity in gastrointestinal cancer 16,17 .…”

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The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene

2005

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KLF4 (GKLF/EZF) encodes a transcription factor that is associated with both tumour suppression and oncogenesis. We describe the identification of KLF4 in a functional genomic screen for genes that bypass RAS V12 -induced senescence. However, in untransformed cells, KLF4 acts as a potent inhibitor of proliferation. KLF4-induced arrest is bypassed by oncogenic RAS V12 or by the RAS target cyclin-D1. Remarkably, inactivation of the cyclin-D1 target and the cell-cycle inhibitor p21 CIP1 not only neutralizes the cytostatic action of KLF4, but also collaborates with KLF4 in oncogenic transformation. Conversely, KLF4 suppresses the expression of p53 by directly acting on its promoter, thereby allowing for RAS V12 -mediated transformation and causing resistance to DNA-damage-induced apoptosis. Consistently, KLF4 depletion from breast cancer cells restores p53 levels and causes p53-dependent apoptosis. These results unmask KLF4 as a regulator of p53 that oncogenically transforms cells as a function of p21 CIP1 status. Furthermore, they provide a mechanistic explanation for the context-dependent oncogenic or tumour-suppressor functions of KLF4.Krüppel-like factor 4 (KLF4/GKLF/EZF) 1,2 is a transcription factor that can both activate and repress genes that are involved in cell-cycle regulation and differentiation. Among the KLF4-regulated cell-cycle genes, many upregulated genes are inhibitors of proliferation, whereas genes that promote proliferation are repressed 3 . This indicates that KLF4 regulates the expression of a set of cell-cycle genes to coordinately inhibit cellular proliferation. In keeping with this is the notion that ectopic expression of KLF4 acts cytostatically 1,4,5 . Moreover, KLF4 levels rise following DNA damage, cell-cycle arrest in response to serum withdrawal and contact inhibition 1,6 . Similarly, KLF4 levels are increased in the post-mitotic compartment of the gut and skin 1,2 . In mice, ectopic expression of Klf4 accelerates terminal differentiation, leading to premature skin-barrier acquisition 7 , whereas Klf4 deficiency prevents the terminal differentiation of colonic goblet cells 8 and the skin epithelium 9 , which leads to neonatal death 9 . These observations establish KLF4 as a stress-and differentiation-associated inhibitor of proliferation 10 , raising the possibility that KLF4 may have tumour-suppressive functions 8,11,12 .Indeed, KLF4 expression is frequently lost in various human cancer types 11,[13][14][15][16][17][18][19] . Recently, KLF4 has been shown to undergo promoter methylation and loss of heterozygosity in gastrointestinal cancer 16,17 . Consistent with a tumour-suppressor function for KLF4, its overexpression reduces the tumorigenicity of colonic and gastric cancer cells in vivo 17,20 . These observations, taken together, indicate that KLF4 acts as a tumour suppressor. This notion is further supported by recent data showing that specific ablation of Klf4 in the gastric epithelium of mice results in premalignant changes, including polypoid lesions 18 .Conversely, elevated K...

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Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer

Cited by 165 publications

References 23 publications

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene

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