Download Gene Section SLC5A8 (solute carrier family 5 member 8)

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in Oncology and Haematology
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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
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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
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solute carrier family 5 member 8 (SLC5A8) in human
pancreatic cancer. Pancreas. 2008 May;36(4):e32-9
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colon of SLC5A8-deficient mice. J Biol Chem. 2008 Sep
5;283(36):24729-37
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cancer cells maintain low levels of pyruvate to avoid cell death
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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)
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