Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer

Muthusamy Thangaraju, Gail Cresci, Shiro Itagaki, John Mellinger, Darren D Browning, Franklin G. Berger, Puttur D Prasad, Vadivel Ganapathy

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Introduction: 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 p85α and upregulation of p55α and p50α. Conclusion: These studies show that SLC5A8 mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in the colon.

Original languageEnglish (US)
Pages (from-to)1773-1781
Number of pages9
JournalJournal of Gastrointestinal Surgery
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2008

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Volatile Fatty Acids
Butyrates
Colonic Neoplasms
Sodium
Colon
Up-Regulation
Down-Regulation
Phosphatidylinositol 3-Kinase
Apoptosis
Intestinal Neoplasms
Neoplasms
Methyltransferases
DNA Methylation
Histones
Genes
Fermentation
Gene Expression
Cell Line
DNA

Keywords

  • Colon cancer
  • Commensal bacteria
  • Dietary fiber
  • DNA methylation
  • Histone deacetylation
  • Tumor suppression

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

Cite this

Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. / Thangaraju, Muthusamy; Cresci, Gail; Itagaki, Shiro; Mellinger, John; Browning, Darren D; Berger, Franklin G.; Prasad, Puttur D; Ganapathy, Vadivel.

In: Journal of Gastrointestinal Surgery, Vol. 12, No. 10, 01.10.2008, p. 1773-1781.

Research output: Contribution to journalArticle

Thangaraju, Muthusamy ; Cresci, Gail ; Itagaki, Shiro ; Mellinger, John ; Browning, Darren D ; Berger, Franklin G. ; Prasad, Puttur D ; Ganapathy, Vadivel. / Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. In: Journal of Gastrointestinal Surgery. 2008 ; Vol. 12, No. 10. pp. 1773-1781.
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