Butyrate suppresses expression of neuropilin I in colorectal cell lines through inhibition of Sp1 transactivation.
BACKGROUND
Neuropilin is a transmembrane receptor for vascular endothelial growth factor (VEGF) and is expressed in normal endothelial cells and upregulated in cancer cells. Neuropilin-1 (NRP-1) has been shown to promote tumour cell migration and survival in colon cancer in response to VEGF binding. The expression profiles of neuropilins, associated co-receptors and known ligands have been mapped in three colorectal cell lines: Caco-2, HCT116 & HT29. We have previously shown that butyrate, a naturally occurring histone deacetylase inhibitor (HDACi) produced by fermentation of fibre in the colon, causes apoptosis of colon cancer cell lines.


RESULTS
Here we demonstrate that butyrate down-regulates NRP-1 and VEGF at the mRNA and protein level in colorectal cancer cell lines. NRP-1 is a known transcriptional target of Sp1, whose activity is regulated by acetylation. NRP-1 down-regulation by butyrate was associated with decreased binding affinity of Sp1 for canonical Sp-binding sites in the NRP-1 promoter. siRNA-mediated knock-down of Sp1 implied that Sp1 may have strong DNA binding activity but weak transactivation potential.


CONCLUSIONS
The downregulation of the key apoptotic and angiogenesis regulator NRP-1 by butyrate suggests a novel contributory mechanism to the chemopreventive effect of dietary fibre.
Department of Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK.
Danny C W
DC
Yu
Jennifer S
JS
Waby
Haridasan
H
Chirakkal
Carolyn A
CA
Staton
Bernard M
BM
Corfe
D002087:Butyrates / Q000494:pharmacology*; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1