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

Oncogene. 2004 Jan 15;23(2):395-402. doi: 10.1038/sj.onc.1207067.

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 p21(WAF1/Cip1) promoter. These findings indicate that KLF4 is a potential tumor suppressor gene in CRC.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • Amino Acid Sequence
  • Base Sequence
  • Blotting, Southern
  • Blotting, Western
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colorectal Neoplasms / genetics*
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor / physiology*
  • Humans
  • Kruppel-Like Transcription Factors
  • Loss of Heterozygosity / genetics
  • Molecular Sequence Data
  • Point Mutation / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • 5' Untranslated Regions
  • DNA-Binding Proteins
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • RNA, Messenger
  • Transcription Factors