Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer.
BACKGROUND
SLC5A8, expressed predominantly in the colon, is a Na(+)-coupled transporter for short-chain fatty acids. In this paper, we report on the characterization of butyrate transport by SLC5A8 and the relevance of SLC5A8-mediated butyrate transport to colon cancer.


RESULTS
SLC5A8 transports butyrate via a Na(+)-dependent electrogenic process. Na(+) activation of the transport process exhibits sigmoidal kinetics, indicating involvement of more than one Na(+) in the activation process. SLC5A8 is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of SLC5A8 involves DNA methylation by DNA methyltransferase 1. Reexpression of SLC5A8 in colon cancer cells leads to apoptosis but only in the presence of butyrate. SLC5A8-mediated entry of butyrate into cancer cells is associated with inhibition of histone deacetylation. The changes in gene expression in SLC5A8/butyrate-induced apoptosis include upregulation of pro-apoptotic genes and downregulation of anti-apoptotic genes. In addition, the expression of phosphatidylinositol-3-kinase subunits is affected differentially, with downregulation of p85alpha and upregulation of p55alpha and p50alpha.


CONCLUSIONS
These studies show that SLC5A8 mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in the colon.
Thangaraju
Muthusamy
M
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
Cresci
Gail
G
Itagaki
Shiro
S
Mellinger
John
J
Browning
Darren D
DD
Berger
Franklin G
FG
Prasad
Puttur D
PD
Ganapathy
Vadivel
V
D000818:Animals; D001693:Biological Transport, Active; D002087:Butyrates / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics*; D006801:Humans; D051379:Mice; D027501:Monocarboxylic Acid Transporters; D012964:Sodium / Q000378:metabolism
D002087:Butyrates; D027682:Cation Transport Proteins; D027501:Monocarboxylic Acid Transporters; C476760:SLC5A8 protein, human; D012964:Sodium