Thangaraju Muthusamy, Cresci Gail, Itagaki Shiro, Mellinger John, Browning Darren D, Berger Franklin G, Prasad Puttur D, Ganapathy Vadivel
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
J Gastrointest Surg. 2008 Oct;12(10):1773-81; discussion 1781-2. doi: 10.1007/s11605-008-0573-0. Epub 2008 Jul 26.
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.
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.
These studies show that SLC5A8 mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in the colon.
SLC5A8主要在结肠中表达，是一种用于短链脂肪酸的Na(+)偶联转运体。在本文中，我们报告了SLC5A8介导的丁酸转运特性以及SLC5A8介导的丁酸转运与结肠癌的相关性。
SLC5A8通过Na(+)依赖性电生成过程转运丁酸。转运过程的Na(+)激活表现出S形动力学，表明在激活过程中有不止一个Na(+)参与。SLC5A8在人类结肠癌、肠道/结肠癌小鼠模型以及结肠癌细胞系中均沉默。SLC5A8与肿瘤相关的沉默涉及DNA甲基转移酶1介导的DNA甲基化。在结肠癌细胞中重新表达SLC5A8会导致细胞凋亡，但仅在有丁酸存在的情况下。SLC5A8介导的丁酸进入癌细胞与组蛋白去乙酰化的抑制有关。SLC5A8/丁酸诱导的细胞凋亡中基因表达的变化包括促凋亡基因的上调和抗凋亡基因的下调。此外，磷脂酰肌醇-3-激酶亚基的表达受到不同影响，p85α下调，p55α和p50α上调。
这些研究表明，SLC5A8介导了细菌发酵产物丁酸在结肠中的肿瘤抑制作用。
