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
SLC5A8
LOCATION
12q23.1
LOCUSID
160728
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.

Article 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
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

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
382878022024Role of SLC5A8 as a Tumor Suppressor in Cervical Cancer.0
382878022024Role of SLC5A8 as a Tumor Suppressor in Cervical Cancer.0
380074462023Role of hypermethylated SLC5A8 in follicular thyroid cancer diagnosis and prognosis prediction.0
380074462023Role of hypermethylated SLC5A8 in follicular thyroid cancer diagnosis and prognosis prediction.0
348804922022Structure and mechanism of the SGLT family of glucose transporters.31
349649462022Lactobacillus plantarum-derived metabolites sensitize the tumor-suppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells.14
348804922022Structure and mechanism of the SGLT family of glucose transporters.31
349649462022Lactobacillus plantarum-derived metabolites sensitize the tumor-suppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells.14
342313932021miR-29a, b, and c regulate SLC5A8 expression in intestinal epithelial cells.3
342313932021miR-29a, b, and c regulate SLC5A8 expression in intestinal epithelial cells.3
320170632020Hypermethylated RASSF1 and SLC5A8 promoters alongside BRAF(V600E) mutation as biomarkers for papillary thyroid carcinoma.12
324327312020SLC5A8 regulates the biological behaviors of cervical cancer cells through mediating the Wnt signaling pathway.3
320170632020Hypermethylated RASSF1 and SLC5A8 promoters alongside BRAF(V600E) mutation as biomarkers for papillary thyroid carcinoma.12
324327312020SLC5A8 regulates the biological behaviors of cervical cancer cells through mediating the Wnt signaling pathway.3
306042882019Identification of the multivalent PDZ protein PDZK1 as a binding partner of sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8) and SMCT2 (SLC5A12).9

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-(solute-carrier-family-5-member-8)