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Nutrient-Gene Interactions

Krüppel-Like Factor 4 Is Transactivated by Butyrate in Colon Cancer Cells¹

Section of Gastroenterology, VA Boston Healthcare System and Boston University School of Medicine, Boston, MA 02118

²To whom correspondence should be addressed. E-mail: zhiyi.chen{at}bmc.org.

High-fiber diets decrease the incidence of colorectal cancers, and SCFA, derived from dietary fiber, are involved in the regulation of cell growth, differentiation, and apoptosis of the colonic epithelium. The mediators of these effects remain poorly defined. Krüppel-like factor-4 (KLF4/GKLF) is a zinc-finger transcription factor that exhibits some physiologic properties similar to those of SCFA in the colon. The present study was undertaken to examine the role of KLF4 in the butyrate-mediated effect in colon cancer HT-29 cells. Butyrate induced KLF4 mRNA expression and stimulated KLF4 promoter activity in a dose- and time-dependent manner in HT-29 cells. Similar effects were observed in SCFA possessing different carbon lengths (C3–C7), but not in branched isobutyric acid, indicating that the stimulatory properties of SCFA were related to fatty acid structure. Transfection studies using 5' deletion and mutant constructs of the KLF4 promoter demonstrated that the butyrate-responsive element was located at a putative stimulatory protein (Sp)1-binding site. Electrophoretic mobility shift assays using an oligonucleotide containing a consensus Sp1-binding element revealed a DNA-protein complex that was enhanced by butyrate treatment and supershifted by the Sp1 antiserum. Furthermore, the effects of butyrate on cell growth and KLF4 mRNA expression were the same as those of trichostatin A (TSA), a specific inhibitor of histone deacetylase (HDAC1). Overexpression of HDAC1 significantly attenuated transcriptional activation of the KLF4 promoter by butyrate or TSA. These results suggest that KLF4 may function as one of the downstream effectors of butyrate that mediates its growth arrest effect in the colon. Moreover, transactivation of KLF4 by butyrate appears to be mediated through interaction with a Sp1-binding domain on the promoter and is also likely to involve histone acetylation.

KEY WORDS: • GKLF/KLF4 • butyrate • histone acetylation • short chain fatty acids

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