SLC5A8 (solute carrier family 5 member 8)
2009-10-01 Julie Di Bernardo , Kerry J Rhoden AffiliationMedical Genetics Unit, Department of Gynaecologic, Obstetric, Pediatric Sciences, University of Bologna, Bologna, Italy
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.
Proteins
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.
- 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.
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).
- 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 ID | Last Year | Title | Authors |
|---|---|---|---|
| 18559491 | 2008 | Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. | Bennett KL et al |
| 15090606 | 2004 | The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. | Coady MJ et al |
| 15389252 | 2005 | Progressive methylation during the serrated neoplasia pathway of the colorectum. | Dong SM et al |
| 18562324 | 2008 | Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice. | Frank H et al |
| 18992769 | 2009 | Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. | Ganapathy V et al |
| 15651982 | 2005 | 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 et al |
| 16375929 | 2006 | SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. | Gupta N et al |
| 15867356 | 2005 | Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. | Hong C et al |
| 16858683 | 2006 | Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. | Hu S et al |
| 12829793 | 2003 | SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. | Li H et al |
| 17591909 | 2007 | Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina. | Martin PM et al |
| 14966140 | 2004 | Functional 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 |
| 18437076 | 2008 | Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer. | Park JY et al |
| 18037591 | 2007 | Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor. | Park JY et al |
| 16670197 | 2006 | Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT. | Paroder V et al |
| 15687339 | 2005 | Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. | Porra V et al |
| 12107270 | 2002 | Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. | Rodriguez AM et al |
| 18789002 | 2009 | Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. | Thangaraju M et al |
| 15361710 | 2004 | Aberrant 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 ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000256870 | ENST00000536262 | Q8N695 |
Expression (GTEx)
Pathways
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38287802 | 2024 | Role of SLC5A8 as a Tumor Suppressor in Cervical Cancer. | 0 |
| 38287802 | 2024 | Role of SLC5A8 as a Tumor Suppressor in Cervical Cancer. | 0 |
| 38007446 | 2023 | Role of hypermethylated SLC5A8 in follicular thyroid cancer diagnosis and prognosis prediction. | 0 |
| 38007446 | 2023 | Role of hypermethylated SLC5A8 in follicular thyroid cancer diagnosis and prognosis prediction. | 0 |
| 34880492 | 2022 | Structure and mechanism of the SGLT family of glucose transporters. | 31 |
| 34964946 | 2022 | Lactobacillus 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 |
| 34880492 | 2022 | Structure and mechanism of the SGLT family of glucose transporters. | 31 |
| 34964946 | 2022 | Lactobacillus 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 |
| 34231393 | 2021 | miR-29a, b, and c regulate SLC5A8 expression in intestinal epithelial cells. | 3 |
| 34231393 | 2021 | miR-29a, b, and c regulate SLC5A8 expression in intestinal epithelial cells. | 3 |
| 32017063 | 2020 | Hypermethylated RASSF1 and SLC5A8 promoters alongside BRAF(V600E) mutation as biomarkers for papillary thyroid carcinoma. | 12 |
| 32432731 | 2020 | SLC5A8 regulates the biological behaviors of cervical cancer cells through mediating the Wnt signaling pathway. | 3 |
| 32017063 | 2020 | Hypermethylated RASSF1 and SLC5A8 promoters alongside BRAF(V600E) mutation as biomarkers for papillary thyroid carcinoma. | 12 |
| 32432731 | 2020 | SLC5A8 regulates the biological behaviors of cervical cancer cells through mediating the Wnt signaling pathway. | 3 |
| 30604288 | 2019 | Identification 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
