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Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer

Abstract

Krüppel-like factor 4 (KLF4 or GKLF) is an inhibitor of the cell cycle. The gene encoding KLF4 is localized on chromosome 9q, previously shown to exhibit allelic loss in colorectal cancer (CRC). In this study, we show that the mean level of KLF4 mRNA in a panel of 30 CRC was 52% that of paired normal colonic tissues. Similarly, the levels of KLF4 mRNA and protein in a panel of six established CRC cell lines were significantly lower than those of an untransformed colonic epithelial cell line. Using highly polymorphic DNA markers that flank the KLF4 locus, we found evidence for loss of heterozygosity (LOH) in two of eight surgically resected CRC specimens. In addition, LOH was observed in five of six CRC cell lines with one additional cell line exhibiting hemizygous deletion in the KLF4 gene. We also found that the 5′-untranslated region of KLF4 was hypermethylated in a subset of resected CRC specimens and cell lines. Lastly, the open-reading frame of KLF4 in two of three CRC cell lines examined contained several point mutations that resulted in a diminished ability to activate the p21WAF1/Cip1 promoter. These findings indicate that KLF4 is a potential tumor suppressor gene in CRC.

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Abbreviations

APC:

adenomatous polyposis coli

CRC:

colorectal cancer

FAP:

familial adenomatous polyposis

GKLF:

gut-enriched Krüppel-like factor

KLF4:

Krüppel-like factor

LOH:

loss of heterozygosity

Min:

multiple intestinal neoplasia

MSP:

methylation-specific polymerase chain reaction

ORF:

open-reading frame

PBS:

phosphate-buffered saline

RT–PCR:

reverse transcription–polymerase chain reaction

UTR:

untranslated region

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Acknowledgements

We thank Dr Bert Vogelstein for providing the full-length cDNA probe for p21WAF1/Cip1. This work was in part supported by grants from the National Institutes of Health (DK52230, DK64399, CA84197). VWY is the recipient of a Georgia Cancer Coalition Distinguished Cancer Clinician Scientist Award.

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Correspondence to Vincent W Yang.

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Zhao, W., Hisamuddin, I., Nandan, M. et al. Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene 23, 395–402 (2004). https://doi.org/10.1038/sj.onc.1207067

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