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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review SLC5A8 (solute carrier family 5 member 8) Julie Di Bernardo, Kerry J Rhoden Medical Genetics Unit, Department of Gynaecologic, Obstetric and Pediatric Sciences, University of Bologna, Bologna, Italy (JDB, KJR) Published in Atlas Database: October 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC5A8ID44089ch12q23.html DOI: 10.4267/2042/44829 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Pseudogene Identity No pseudogenes identified. Other names: AIT; MGC125354; SMCT; SMCT1 HGNC (Hugo): SLC5A8 Location: 12q23.2 Local order: Telomeric to TMEM16D, centromeric to UTP20. Protein Description 610 amino acids; 66,560 Da; 13 transmembrane domains, extracellular N-terminal, cytosolic Cterminal. DNA/RNA Expression Description Gastrointestinal tract (stomach, colon, ileum), kidney, thyroid, brain, retina, breast, prostate, salivary gland ducts. 15 exons, spanning 54023 bp. Transcription 3286 bases, open reading frame: 1833 bp. No alternative splicing variants have been reported. SLC5A8 transcription is regulated by hypermethylation of CpG-rich islands in the promoter region. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) Localisation Cell membrane; apical membrane in thyrocytes and colonocytes. 781 SLC5A8 (solute carrier family 5 member 8) Di Bernardo J, Rhoden KJ Diagram drawn following UniProtKB/Swiss-Prot database prediction and maintaining approximate length proportions among extracellular and intracellular segments. Transmembrane segments are represented by rectangles. a sodium/monocarboxylate transporter; 46% identity with SLC5A5, the Sodium-Iodide Symporter. Function Sodium coupled transport of short-chain monocarboxylates, including lactate, butyrate, pyruvate, acetate, proprionate, ketone bodies and nicotinate. The sodium/substrate stoichiometry depends on the transported substrate. SLC5A8 is considered a tumor suppressor, and its expression is downregulated in several kinds of tumor. Its tumor suppressor activity may be due to its ability to transport and accumulate histone deacetylase inhibitors such as butyrate and pyruvate. - Gastrointestinal tract: colonocyte absorption and accumulation of short chain fatty acids produced by bacteria in the intestinal lumen. In particular, butyrate and pyruvate are inhibitors of histone deacetylases and are known to promote differentiation in normal colon epithelial cells but selectively induce apoptosis in tumor cells. - Kidney: lactate transport; reabsorption of lactate from urine to blood. - Thyroid: unknown function. When first identified, SLC5A8 was shown to localize on the apical membrane of thyrocytes and to transport iodide by a passive mechanism. Lately, this evidence has been rejected by different groups that showed that iodide is not a SLC5A8 substrate. - Brain: transport of lactate and ketone bodies; role in energy maintenance in neurons. Mutations Germinal No germinal mutations implicated in human disease to date. SLC5A8 knockout mouse (deletion of exons 4 and 5) is viable and fertile, with no evident malformation; affected by lactaturia and loss of sodium-dependent lactate uptake in the colon. Somatic No somatic mutations implicated in human disease to date. Implicated in Colorectal cancer Prognosis SLC5A8 expression may be a favorable indicator of colorectal cancer prognosis; higher expression correlates with longer disease-free survival (Paroder et al., 2006). Oncogenesis SLC5A8 is expressed in normal colon, but is silenced in colon cancer due to gene methylation. SLC5A8 exerts a tumor suppressor function, possibly due to its ability to transport and accumulate histone deacetylase inhibitors such as butyrate and pyruvate. - 59% of primary colon cancers and colonic adenomas (dysplastic polyps, precursor lesions of colon cancer), and 52% of colon cancer cell lines show aberrant methylation of SLC5A8 exon 1 (Li et al., 2003). Homology Belongs to the SLC superfamily of solute carriers; the SLC5 family has 12 members to date (SLC5A1SLC5A12) and includes Na+-coupled cotransporters that rely on the Na+ electrochemical gradient to drive solute transport into cells. 53% identity with SLC5A12, Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 782 SLC5A8 (solute carrier family 5 member 8) Di Bernardo J, Rhoden KJ tumour suppressor gene SLC5A8 expresses a Na+monocarboxylate cotransporter. J Physiol. 2004 Jun 15;557(Pt 3):719-31 - 82,5% of serrated adenomas (polyps with mixed hyperplastic/adenomatous features, precursor lesions of colon cancer), exhibit tumor-specific promoter methylation of SLC5A8; methylation of CpG islands increases with the histological progression of serrated adenomas (Dong et al., 2005). - 66.4% of Duke C stage colorectal cancers (i.e. colorectal cancer with lymph node metastases) express low levels of SLC5A8 (Paroder et al., 2006). Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin P, Smith SB, Prasad PD, Ganapathy V. Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate. J Biol Chem. 2004 Oct 22;279(43):44522-32 Miyauchi S, Gopal E, Fei YJ, Ganapathy V. Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids. J Biol Chem. 2004 Apr 2;279(14):13293-6 Papillary thyroid cancer (PTC) Ueno M, Toyota M, Akino K, Suzuki H, Kusano M, Satoh A, Mita H, Sasaki Y, Nojima M, Yanagihara K, Hinoda Y, Tokino T, Imai K. Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer. Tumour Biol. 2004 May-Jun;25(3):134-40 Prognosis SLC5A8 methylation and silencing of gene expression is significantly associated with aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality and advanced tumor stages (Hu et al., 2006). Oncogenesis SLC5A8 expression is selectively down-regulated in papillary thyroid carcinomas: SLC5A8 is methylated in 90% of classical PTC and in 20% of other PTC subtypes, including the follicular variant. SLC5A8 methylation and low expression is highly associated with the prescence of the BRAF T1796A mutation (Porra et al., 2005; Hu et al., 2006). Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM. Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol. 2005 Feb;18(2):170-8 Ganapathy V, Gopal E, Miyauchi S, Prasad PD. Biological functions of SLC5A8, a candidate tumour suppressor. Biochem Soc Trans. 2005 Feb;33(Pt 1):237-40 Gopal E, Fei YJ, Miyauchi S, Zhuang L, Prasad PD, Ganapathy V. Sodium-coupled and electrogenic transport of Bcomplex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family. Biochem J. 2005 May 15;388(Pt 1):309-16 Hong C, Maunakea A, Jun P, Bollen AW, Hodgson JG, Goldenberg DD, Weiss WA, Costello JF. Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. Cancer Res. 2005 May 1;65(9):3617-23 Various cancers Disease Acute myeloid leukemia (AML), astrocytoma and oligodendroglioma, breast cancer, gastric cancer, head and neck squamous cells carcinoma, pancreatic cancer, prostate cancer. Oncogenesis SLC5A8 expression is decreased in various cancers due to DNA methylation in the SLC5A8 promoter region. Porra V, Ferraro-Peyret C, Durand C, Selmi-Ruby S, Giroud H, Berger-Dutrieux N, Decaussin M, Peix JL, Bournaud C, Orgiazzi J, Borson-Chazot F, Dante R, Rousset B. Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab. 2005 May;90(5):3028-35 Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci. 2006 Apr 18;78(21):2419-25 To be noted Note Several single nucleotide polymorphisms have been found, mostly in introns, or resulting in synonymous codons with no change in amino acid. A single nonsynonymous coding polymorphism (Phe251Val) has been reported to negatively affect transport activity. Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V, Xing M. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006 Nov 15;119(10):2322-9 References Paroder V, Spencer SR, Paroder M, Arango D, Schwartz S Jr, Mariadason JM, Augenlicht LH, Eskandari S, Carrasco N. Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT. Proc Natl Acad Sci U S A. 2006 May 9;103(19):7270-5 Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab. 2002 Jul;87(7):3500-3 Thangaraju M, Gopal E, Martin PM, Ananth S, Smith SB, Prasad PD, Sterneck E, Ganapathy V. SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res. 2006 Dec 15;66(24):11560-4 Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko RM, Casey G, Issa JP, Willis J, Willson JK, Plass C, Markowitz SD. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8412-7 Martin PM, Dun Y, Mysona B, Ananth S, Roon P, Smith SB, Ganapathy V. Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina. Invest Ophthalmol Vis Sci. 2007 Jul;48(7):3356-63 Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B, Sah JF, Markowitz SD, Romero MF, Lapointe JY. The human Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 783 SLC5A8 (solute carrier family 5 member 8) Di Bernardo J, Rhoden KJ Park JY, Zheng W, Kim D, Cheng JQ, Kumar N, Ahmad N, Pow-Sang J. Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor. Cancer Detect Prev. 2007;31(5):359-65 solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer. Pancreas. 2008 May;36(4):e32-9 Thangaraju M, Cresci G, Itagaki S, Mellinger J, Browning DD, Berger FG, Prasad PD, Ganapathy V. Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. J Gastrointest Surg. 2008 Oct;12(10):1773-81; discussion 1781-2 Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, Plinkert P, Herpel E, Smiraglia D, Plass C. Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res. 2008 Jun 15;68(12):4494-9 Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther. 2009 Jan;121(1):29-40 Frank H, Gröger N, Diener M, Becker C, Braun T, Boettger T. Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice. J Biol Chem. 2008 Sep 5;283(36):24729-37 Thangaraju M, Carswell KN, Prasad PD, Ganapathy V. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem J. 2009 Jan 1;417(1):379-89 Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008;10(1):193-9 This article should be referenced as such: Di Bernardo J, Rhoden KJ. SLC5A8 (solute carrier family 5 member 8). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):781-784. Park JY, Helm JF, Zheng W, Ly QP, Hodul PJ, Centeno BA, Malafa MP. Silencing of the candidate tumor suppressor gene Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 784