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

60 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

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