SLC5A8 (solute carrier family 5 member 8)

2009-10-01   Julie Di Bernardo , Kerry J Rhoden 

Medical Genetics Unit, Department of Gynaecologic, Obstetric, Pediatric Sciences, University of Bologna, Bologna, Italy

Identity

HGNC
LOCATION
12q23.1
LOCUSID
ALIAS
AIT,SMCT,SMCT1

DNA/RNA

Atlas Image

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.

Proteins

Atlas Image
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

Entity name
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 name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
185594912008Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma.Bennett KL et al
150906062004The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter.Coady MJ et al
153892522005Progressive methylation during the serrated neoplasia pathway of the colorectum.Dong SM et al
185623242008Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice.Frank H et al
189927692009Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond.Ganapathy V et al
156519822005Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family.Gopal E et al
163759292006SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter.Gupta N et al
158673562005Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8.Hong C et al
168586832006Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer.Hu S et al
128297932003SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers.Li H et al
175919092007Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina.Martin PM et al
149661402004Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids.Miyauchi S et al
184370762008Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer.Park JY et al
180375912007Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor.Park JY et al
166701972006Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT.Paroder V et al
156873392005Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas.Porra V et al
121072702002Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes.Rodriguez AM et al
187890022009Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3.Thangaraju M et al
153617102004Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer.Ueno M et al

Other Information

Locus ID:

NCBI: 160728
MIM: 608044
HGNC: 19119
Ensembl: ENSG00000256870

Variants:

dbSNP: 160728
ClinVar: 160728
TCGA: ENSG00000256870
COSMIC: SLC5A8

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000256870ENST00000536262Q8N695

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Transmembrane transport of small moleculesREACTOMER-HSA-382551
SLC-mediated transmembrane transportREACTOMER-HSA-425407
Transport of inorganic cations/anions and amino acids/oligopeptidesREACTOMER-HSA-425393
Organic anion transportersREACTOMER-HSA-428643
MetabolismREACTOMER-HSA-1430728
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Metabolism of water-soluble vitamins and cofactorsREACTOMER-HSA-196849
Nicotinate metabolismREACTOMER-HSA-196807
Nicotinamide salvagingREACTOMER-HSA-197264

References

Pubmed IDYearTitleCitations
128297932003SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers.85
149661402004Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids.74
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
168586832006Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer.55
163759292006SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter.54
185594912008Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma.50
166701972006Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT.43
172456492007Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract.34
186611922008Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer.34
204039972010Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer.30

Citation

Julie Di Bernardo ; Kerry J Rhoden

SLC5A8 (solute carrier family 5 member 8)

Atlas Genet Cytogenet Oncol Haematol. 2009-10-01

Online version: http://atlasgeneticsoncology.org/gene/44089/slc5a8