Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line.
Over-expression of the adhesion molecule CD44 and its splice variants, especially CD44v6, is associated with poor prognosis and metastasis. We aimed at regulating the expression of CD44 in the highly metastatic human colon cancer cell line HM7 and thereby affecting its metastatic ability. HM7 cells show constitutive expression of CD44 standard and variants isoforms, which were significantly down-regulated by treatment with butyrate. Butyrate significantly inhibited transcription of the CD44 gene and abolished epidermal growth factor-mediated up-regulation of the reporter gene luciferase subcloned upstream to the CD44 promoter (-1.1 kb) and transfected to HM7 cells. Nuclear proteins from butyrate-treated cells bound to an epidermal growth factor receptor element motif present in the CD44 promoter. Epidermal growth factor receptor element-site directed mutations eliminated the inducibility of the luciferase reporter gene and did not allowed binding of nuclear proteins harvested from butyrate-treated cells. Butyrate induced CD44 gene repression by specifically interacting with an epidermal growth factor receptor element nuclear transcriptional factor. This interaction affects CD44 transcriptional activity vis-à-vis in vivo metastatic ability of HM7 cells. These results provide additional insight into the anticarcinogenic properties of butyrate.
Barshishat
M
M
Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100 Israel.
Levi
I
I
Benharroch
D
D
Schwartz
B
B
D002087:Butyrates / Q000494:pharmacology*; D002277:Carcinoma / Q000473:pathology*; D003110:Colonic Neoplasms / Q000473:pathology*; D017931:DNA Primers; D015536:Down-Regulation; D066246:ErbB Receptors / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D002087:Butyrates; D017931:DNA Primers; D018960:Hyaluronan Receptors; D066246:ErbB Receptors