Role of gut-enriched Krüppel-like factor in colonic cell growth and differentiation

Abstract

Cancer cells differ from normal cells in many aspects, including hyperproliferation and loss of differentiation. Recent research has focused on the role of transcription factors in regulating abnormal cell growth. Gut-enriched Krüppel-like factor (GKLF) is a newly identified eukaryotic zinc finger protein expressed extensively in the gastrointestinal tract. In the current study, we demonstrated that GKLF mRNA levels were significantly decreased in the dysplastic epithelium of the colon, including adenomatous polyp and cancer. GKLF immunostains in the normal colon were higher at the surface epithelium and gradually decreased toward the crypt, but this gradient was not present in the adenomatous and cancerous mucosa. Constitutive overexpression of GKLF DNA in a human colonic adenocarcinoma cell line (HT-29) decreased [(3)H]thymidine incorporation, whereas suppression of GKLF gene increased DNA synthesis, indicating that downregulation of the GKLF gene might contribute to cellular hyperproliferation. Cyclin D1 (CD1) protein level and CD1-associated kinase activity were decreased in HT-29 cell overexpressed GKLF cDNA, and CD1 promoter activity was profoundly suppressed by GKLF. When HT-29 cells were cultured in the presence of sodium butyrate, GKLF mRNA levels increased as cells acquired more differentiated phenotypes. These results suggest that GKLF plays an important role in regulating cell growth and differentiation in the colonic epithelium and that downregulation of GKLF expression may cause colonic cells to become hyperproliferative. Furthermore, GKLF appears to be a transcriptional repressor of the CD1 gene.

The Loss of Sarco/Endoplasmic Reticulum Calcium Transport ATPase 3 Expression Is an Early Event during the Multistep Process of Colon Carcinogenesis

“…This family comprises more than 20 members, including Sp1, Sp2, Sp3, Sp4, and various Krü ppel-like factors including the gut-enriched Krü ppel-like factor, GKLF. 51 Sp1-like factors are involved in epithelial differentiation in the colon, [52][53][54] and their expression has been shown to be perturbed in dysplastic lesions and carcinoma. 53,55 Sp1-like factors possess distinct transcriptional activities and may associate with other transcription factors and histone modifying enzymes.…”

“…51 Sp1-like factors are involved in epithelial differentiation in the colon, [52][53][54] and their expression has been shown to be perturbed in dysplastic lesions and carcinoma. 53,55 Sp1-like factors possess distinct transcriptional activities and may associate with other transcription factors and histone modifying enzymes. 51,56 Their activity may be modulated by enzymatic modifications including acetylation and has been shown to be altered by histone deacetylase inhibitors such as butyrate.…”

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

“…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 .…”

“…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 .…”

Transcriptional regulation of A33 antigen expression by gut-enriched Krüppel-like factor

“…In vitro studies have suggested that GKLF plays an important role in cell proliferation and/or differentiation (Shie et al, 2000b). However, gene ablation in mice leads to a specific deficiency in the barrier function of the skin, resulting in postnatal death.…”