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SLC5A8 (solute carrier family 5 member 8)

Written2009-10Julie Di Bernardo, Kerry J Rhoden
Medical Genetics Unit, Department of Gynaecologic, Obstetric, Pediatric Sciences, University of Bologna, Bologna, Italy

(Note : for Links provided by Atlas : click)

Identity

Alias_namessolute carrier family 5 (iodide transporter), member 8
solute carrier family 5 (sodium/monocarboxylate cotransporter), member 8
Alias_symbol (synonym)AIT
Other aliasMGC125354
SMCT
SMCT1
HGNC (Hugo) SLC5A8
LocusID (NCBI) 160728
Atlas_Id 44089
Location 12q23.1  [Link to chromosome band 12q23]
Location_base_pair Starts at 101156216 and ends at 101210238 bp from pter ( according to hg19-Feb_2009)  [Mapping SLC5A8.png]
Local_order Telomeric to TMEM16D, centromeric to UTP20.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

 
Description 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.
Pseudogene No pseudogenes identified.

Protein

 
  Diagram drawn following UniProtKB/Swiss-Prot database prediction and maintaining approximate length proportions among extracellular and intracellular segments. Transmembrane segments are represented by rectangles.
Description 610 amino acids; 66,560 Da; 13 transmembrane domains, extracellular N-terminal, cytosolic C-terminal.
Expression Gastrointestinal tract (stomach, colon, ileum), kidney, thyroid, brain, retina, breast, prostate, salivary gland ducts.
Localisation Cell membrane; apical membrane in thyrocytes and colonocytes.
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.
Homology Belongs to the SLC superfamily of solute carriers; the SLC5 family has 12 members to date (SLC5A1-SLC5A12) and includes Na+-coupled cotransporters that rely on the Na+ electrochemical gradient to drive solute transport into cells. 53% identity with SLC5A12, a sodium/monocarboxylate transporter; 46% identity with SLC5A5, the Sodium-Iodide Symporter.

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

Note
  
Entity 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).
- 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).
  
  
Entity Papillary thyroid cancer (PTC)
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).
  
  
Entity 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.
  

To be noted

Several single nucleotide polymorphisms has 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.

Bibliography

Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma.
Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, Plinkert P, Herpel E, Smiraglia D, Plass C.
Cancer Res. 2008 Jun 15;68(12):4494-9.
PMID 18559491
 
The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter.
Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B, Sah JF, Markowitz SD, Romero MF, Lapointe JY.
J Physiol. 2004 Jun 15;557(Pt 3):719-31.
PMID 15090606
 
Progressive methylation during the serrated neoplasia pathway of the colorectum.
Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM.
Mod Pathol. 2005 Feb;18(2):170-8.
PMID 15389252
 
Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice.
Frank H, Groger N, Diener M, Becker C, Braun T, Boettger T.
J Biol Chem. 2008 Sep 5;283(36):24729-37
PMID 18562324
 
Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond.
Ganapathy V, Thangaraju M, Prasad PD.
Pharmacol Ther. 2009 Jan;121(1):29-40. (REVIEW)
PMID 18992769
 
Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family.
Gopal E, Fei YJ, Miyauchi S, Zhuang L, Prasad PD, Ganapathy V.
Biochem J. 2005 May 15;388(Pt 1):309-16.
PMID 15651982
 
SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter.
Gupta N, Martin PM, Prasad PD, Ganapathy V.
Life Sci. 2006 Apr 18;78(21):2419-25. (REVIEW)
PMID 16375929
 
Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8.
Hong C, Maunakea A, Jun P, Bollen AW, Hodgson JG, Goldenberg DD, Weiss WA, Costello JF.
Cancer Res. 2005 May 1;65(9):3617-23.
PMID 15867356
 
Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer.
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.
Int J Cancer. 2006 Nov 15;119(10):2322-9.
PMID 16858683
 
SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers.
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.
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8412-7.
PMID 12829793
 
Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina.
Martin PM, Dun Y, Mysona B, Ananth S, Roon P, Smith SB, Ganapathy V.
Invest Ophthalmol Vis Sci. 2007 Jul;48(7):3356-63.
PMID 17591909
 
Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na+-coupled transporter for short-chain fatty acids.
Miyauchi S, Gopal E, Fei YJ, Ganapathy V.
J Biol Chem. 2004 Apr 2;279(14):13293-6.
PMID 14966140
 
Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer.
Park JY, Helm JF, Zheng W, Ly QP, Hodul PJ, Centeno BA, Malafa MP.
Pancreas. 2008 May;36(4):e32-9.
PMID 18437076
 
Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor.
Park JY, Zheng W, Kim D, Cheng JQ, Kumar N, Ahmad N, Pow-Sang J.
Cancer Detect Prev. 2007;31(5):359-65.
PMID 18037591
 
Na+/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT.
Paroder V, Spencer SR, Paroder M, Arango D, Schwartz S Jr, Mariadason JM, Augenlicht LH, Eskandari S, Carrasco N.
Proc Natl Acad Sci U S A. 2006 May 9;103(19):7270-5.
PMID 16670197
 
Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas.
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.
J Clin Endocrinol Metab. 2005 May;90(5):3028-35.
PMID 15687339
 
Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes.
Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T.
J Clin Endocrinol Metab. 2002 Jul;87(7):3500-3.
PMID 12107270
 
Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3.
Thangaraju M, Carswell KN, Prasad PD, Ganapathy V.
Biochem J. 2009 Jan 1;417(1):379-89.
PMID 18789002
 
Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer.
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.
Tumour Biol. 2004 May-Jun;25(3):134-40.
PMID 15361710
 

Citation

This paper 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.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SLC5A8ID44089ch12q23.html


External links

Nomenclature
HGNC (Hugo)SLC5A8   19119
Cards
AtlasSLC5A8ID44089ch12q23
Entrez_Gene (NCBI)SLC5A8  160728  solute carrier family 5 member 8
AliasesAIT; SMCT; SMCT1
GeneCards (Weizmann)SLC5A8
Ensembl hg19 (Hinxton)ENSG00000256870 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000256870 [Gene_View]  chr12:101156216-101210238 [Contig_View]  SLC5A8 [Vega]
ICGC DataPortalENSG00000256870
TCGA cBioPortalSLC5A8
AceView (NCBI)SLC5A8
Genatlas (Paris)SLC5A8
WikiGenes160728
SOURCE (Princeton)SLC5A8
Genetics Home Reference (NIH)SLC5A8
Genomic and cartography
GoldenPath hg38 (UCSC)SLC5A8  -     chr12:101156216-101210238 -  12q23.1-q23.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SLC5A8  -     12q23.1-q23.2   [Description]    (hg19-Feb_2009)
EnsemblSLC5A8 - 12q23.1-q23.2 [CytoView hg19]  SLC5A8 - 12q23.1-q23.2 [CytoView hg38]
Mapping of homologs : NCBISLC5A8 [Mapview hg19]  SLC5A8 [Mapview hg38]
OMIM608044   
Gene and transcription
Genbank (Entrez)AF536216 AK075263 AK313788 AY081220 BC110492
RefSeq transcript (Entrez)NM_145913
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SLC5A8
Cluster EST : UnigeneHs.444536 [ NCBI ]
CGAP (NCI)Hs.444536
Alternative Splicing GalleryENSG00000256870
Gene ExpressionSLC5A8 [ NCBI-GEO ]   SLC5A8 [ EBI - ARRAY_EXPRESS ]   SLC5A8 [ SEEK ]   SLC5A8 [ MEM ]
Gene Expression Viewer (FireBrowse)SLC5A8 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)160728
GTEX Portal (Tissue expression)SLC5A8
Human Protein AtlasENSG00000256870-SLC5A8 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8N695   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8N695  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8N695
Splice isoforms : SwissVarQ8N695
PhosPhoSitePlusQ8N695
Domaine pattern : Prosite (Expaxy)NA_SOLUT_SYMP_3 (PS50283)   
Domains : Interpro (EBI)Na/solute_symporter   
Domain families : Pfam (Sanger)SSF (PF00474)   
Domain families : Pfam (NCBI)pfam00474   
Conserved Domain (NCBI)SLC5A8
DMDM Disease mutations160728
Blocks (Seattle)SLC5A8
SuperfamilyQ8N695
Human Protein Atlas [tissue]ENSG00000256870-SLC5A8 [tissue]
Peptide AtlasQ8N695
HPRD10475
IPIIPI00166969   
Protein Interaction databases
DIP (DOE-UCLA)Q8N695
IntAct (EBI)Q8N695
FunCoupENSG00000256870
BioGRIDSLC5A8
STRING (EMBL)SLC5A8
ZODIACSLC5A8
Ontologies - Pathways
QuickGOQ8N695
Ontology : AmiGOplasma membrane  ion transport  sodium ion transport  apoptotic process  monocarboxylic acid transmembrane transporter activity  symporter activity  monocarboxylic acid transport  integral component of membrane  apical plasma membrane  passive transmembrane transporter activity  NAD biosynthesis via nicotinamide riboside salvage pathway  transmembrane transport  extracellular exosome  
Ontology : EGO-EBIplasma membrane  ion transport  sodium ion transport  apoptotic process  monocarboxylic acid transmembrane transporter activity  symporter activity  monocarboxylic acid transport  integral component of membrane  apical plasma membrane  passive transmembrane transporter activity  NAD biosynthesis via nicotinamide riboside salvage pathway  transmembrane transport  extracellular exosome  
NDEx NetworkSLC5A8
Atlas of Cancer Signalling NetworkSLC5A8
Wikipedia pathwaysSLC5A8
Orthology - Evolution
OrthoDB160728
GeneTree (enSembl)ENSG00000256870
Phylogenetic Trees/Animal Genes : TreeFamSLC5A8
HOVERGENQ8N695
HOGENOMQ8N695
Homologs : HomoloGeneSLC5A8
Homology/Alignments : Family Browser (UCSC)SLC5A8
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSLC5A8 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SLC5A8
dbVarSLC5A8
ClinVarSLC5A8
1000_GenomesSLC5A8 
Exome Variant ServerSLC5A8
ExAC (Exome Aggregation Consortium)ENSG00000256870
GNOMAD BrowserENSG00000256870
Genetic variants : HAPMAP160728
Genomic Variants (DGV)SLC5A8 [DGVbeta]
DECIPHERSLC5A8 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSLC5A8 
Mutations
ICGC Data PortalSLC5A8 
TCGA Data PortalSLC5A8 
Broad Tumor PortalSLC5A8
OASIS PortalSLC5A8 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSLC5A8  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSLC5A8
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SLC5A8
DgiDB (Drug Gene Interaction Database)SLC5A8
DoCM (Curated mutations)SLC5A8 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SLC5A8 (select a term)
intoGenSLC5A8
NCG5 (London)SLC5A8
Cancer3DSLC5A8(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM608044   
Orphanet
MedgenSLC5A8
Genetic Testing Registry SLC5A8
NextProtQ8N695 [Medical]
TSGene160728
GENETestsSLC5A8
Target ValidationSLC5A8
Huge Navigator SLC5A8 [HugePedia]
snp3D : Map Gene to Disease160728
BioCentury BCIQSLC5A8
ClinGenSLC5A8
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD160728
Chemical/Pharm GKB GenePA134989874
Clinical trialSLC5A8
Miscellaneous
canSAR (ICR)SLC5A8 (select the gene name)
Probes
Litterature
PubMed39 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSLC5A8
EVEXSLC5A8
GoPubMedSLC5A8
iHOPSLC5A8
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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