Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity

Dang, Duyen T.; Chen, Xinming; Jin, Feng; Torbenson, Michael; Dang, Long H.; Yang, Vincent W.

doi:10.1038/sj.onc.1206413

Cited by 148 publications

(133 citation statements)

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“…In addition, KLF4 can inhibit pancreatic cancer metastasis in vivo (23). Consistent with these results, KLF4 overexpression reduces cell migration and invasion in RKO colon cancer cells (29). These observations, taken together, indicate that KLF4 has a negative role in migration and invasion of cancer cells, which is opposite to the positive role of miR-10b.…”

Section: Discussionsupporting

confidence: 63%

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MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

Tian

Luo

Cai

et al. 2010

Journal of Biological Chemistry

270

203

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Recently, microRNAs have emerged as regulators of cancer metastasis through acting on multiple signaling pathways involved in metastasis. In this study, we have analyzed the level of miR-10b and cell motility and invasiveness in several human esophageal squamous cell carcinoma cell lines. Our results reveal a significant correlation of miR-10b level with cell motility and invasiveness. Overexpression of miR-10b in KYSE140 cells increased cell motility and invasiveness, whereas inhibition of miR-10b in EC9706 cells reduced cell invasiveness, although it did not alter cell motility. Additionally, we identified KLF4, a known tumor suppressor gene that has been reported to suppress esophageal cancer cell migration and invasion, as a direct target of miR-10b. MicroRNAs, a class of small noncoding RNAs, have been identified as a new kind of gene expression regulators through targeting mRNAs for translational repression or cleavage (1-3). Lately, emerging evidence suggests important roles for miRNAs 2 in apoptosis (4), hematopoietic development (5), cell proliferation (6), skin morphogenesis (7), and neural development (8). Deregulation of miRNAs has also been reported in a variety of tumors, including breast cancer, leukemia, lung cancer, and colon cancer (9 -11), which indicated a significant correlation between miRNAs and human malignancy. miRNA expression profiling in esophageal cancers revealed a distinct miRNA signature (12, 13), and some miRNAs showed correlation with several clinicopathologic parameters (13). Furthermore, miR-21 is reported to regulate the proliferation and invasion in ESCC (14), and the miR-106b-25 polycistron is activated by genomic amplification and is potentially involved in esophageal neoplastic progression (15), providing evidence of a causal role for miRNAs in esophageal cancer development.Recent studies show that miRNAs may act as activators or inhibitors of tumor metastasis by acting on multiple signaling pathways involved in metastasis (16 -18). Ma et al. (16) found that miR-10b initiates invasion and metastasis in breast cancer. miR10b, induced by the prometastatic transcription factor TWIST1, proceeds to inhibit translation of mRNA of HOXD10, a transcription factor already known for its roles in cell motility (19), resulting in increased expression of a pro-metastatic gene, RHOC. This study has provided the first evidence for a role of miRNA in tumor metastasis. Subsequently several additional miRNAs have been reported to act on various steps of metastasis (17, 18).Krüppel-like factor 4 (KLF4), a zinc finger protein of the Krüp-pel-like factor family, plays a role in cell cycle regulation, differentiation, and rises in response to DNA damage, serum starvation, and contact inhibition (20, 21). In line with these studies, the loss of KLF4 expression has been reported in several human tumors, including colorectal, stomach, esophageal, and bladder cancers (22-25), which indicates its tumor suppressor role. However, KLF4 also exhibits oncogenic properties. Overexpression of KLF4 could b...

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Section: Discussionsupporting

confidence: 63%

“…Overexpression of KLF4 could be detected in oropharynx (26) and mammary carcinomas (27). Moreover, it has been reported to inhibit metastasis of several cancers, including esophageal (28), pancreatic (23), and colorectal cancer cells (29). In addition, KLF4 mRNA is targeted by miR-145 (30), implicating the post-transcriptional control of KLF4.…”

mentioning

confidence: 99%

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

Tian

Luo

Cai

et al. 2010

Journal of Biological Chemistry

270

203

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“…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.…”

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confidence: 77%

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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“…Moreover, there is evidence for loss of heterozygosity (LOH) in the KLF4 locus in a subset of colorectal cancer specimens [23]. Conversely, re-expression of KLF4 in a colorectal cancer cell line results in diminished tumorigenecity [24]. Collectively, these findings indicate that KLF4 is a potential tumor suppressor in colorectal cancer.…”

Section: Klf4 and 5 Exhibit Contrasting Effects On Cellular Proliferamentioning

confidence: 98%

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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Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity

Cited by 148 publications

References 31 publications

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

MicroRNA-10b Promotes Migration and Invasion through KLF4 in Human Esophageal Cancer Cell Lines

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

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

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