Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes    Leukemias    Solid Tumours    Cancer-Prone    Deep Insight    Case Reports    Journals   Portal    Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA
    

SLC5A8 and its role in tumorigenesis

 

Kerry J. Rhoden

Medical Genetics Unit, Department of Gynecologic, Obstetric and Pediatric Sciences,
University of Bologna, Policlinico S. Orsola-Malpighi, via Massarenti 9, Bologna 40138, Italy
kerry.rhoden@unibo.it

 

December 2011

 

The solute carrier family-5 member-8 (SLC5A8), identified simultaneously as a transporter and as a tumour suppressor (Rodriguez et al., 2002; Li et al., 2003), has drawn attention for its potential role in tumorigenesis at several sites, and as a potential prognostic marker and therapeutic target in neoplastic disease.

SLC5A8 expression and function in normal tissues

SLC5A8 belongs to the SLC5 family of sodium-coupled transporters which includes at least 12 structurally-related members with diverse tissue distribution and substrate specificity. SLC5A8, in particular, is a sodium-coupled monocarboxylate transporter (also known as SMCT1) predominantly found in the small intestine, colon, thyroid gland, kidney and salivary glands, and to a lesser extent in the retina and brain (Rodriguez et al., 2002; Gopal et al., 2004; Takebe et al., 2005; Iwanaga et al., 2006; Martin et al., 2006; Gopal et al., 2007; Martin et al., 2007; Frank et al., 2008). Electrophysiological and radiotracer studies in cells expressing recombinant SLC5A8 have demonstrated its ability to transport monocarboxylates such as butyrate, proprionate, acetate, lactate, pyruvate, and nicotinate (a B-complex vitamin) (Coady et al., 2004; Miyauchi et al., 2004; Gopal et al., 2004; Gopal et al., 2005), as well as ketone bodies and the amino acid derivative pyroglutamate (Martin et al., 2006; Miyauchi et al., 2010). Substrates are cotransported with sodium into cells, following the inward electrochemical gradient for sodium ions maintained by the sodium-potassium ATPase. Transport is electrogenic, due to a 2:1 Na+:monocarboxylate stoichiometry that results in the transfer of net positive charge into cells (Coady et al., 2007).

The major cotransported substrate for SLC5A8 likely varies from one tissue to another. In the colon, bacterial fermentation of unabsorbed carbohydrates and dietary fiber generates elevated levels of short chain fatty acids (SCFA), primarily acetate, proprionate and butyrate, all of which are SLC5A8 substrates in cellular models. SCFA are necessary for optimal colonic health and are thought to play a significant role in the prevention of gastrointestinal disorders, cancer and cardiovascular disease (Topping and Clifton, 2001; Wong et al., 2006). These effects result primarily from uptake and subsequent metabolism by colonocytes, although SCFA and their metabolites also target other tissues. Butyrate, in particular, is the major fuel for colonocyte metabolism, promotes colonocyte differentiation, and modulates colonic blood flow and electrolyte and water uptake. Acetate is the primary substrate for cholesterol synthesis in the liver, whereas proprionate is a substrate for hepatic gluconeogenesis and inhibits cholesterol synthesis.

SCFA are considered to be the primary substrates for colonic SLC5A8, however, recent data indicates that butyrate and proprionate transport in the colon is not altered in SLC5A8 knockout mice, probably reflecting dominant uptake by other transporters (e.g. SCFA/HCO3- exchange) or by non-ionic diffusion (Frank et al., 2008). Although this result may question the role of SLC5A8 in SCFA uptake in vivo, gene knockout may invoke compensatory mechanisms that mask the true physiological role of the gene product in question. In contrast, SLC5A8 knockout significantly attenuated lactate transport by colonic tissues, suggesting a role for SLC5A8 in intestinal lactate absorption, for example under pathological conditions of bacterial overgrowth leading to D-lactic acidosis (Frank et al., 2008).

Lactate is the preferred substrate for SLC5A8 in the kidney and salivary glands (Gopal et al., 2004; Frank et al., 2008); indeed, SLC5A8 knockout mice manifest higher urinary and salivary lactate concentrations compared to wild-type animals, suggesting that SLC5A8 contributes to lactate reabsorbtion by both organs (Frank et al., 2008). Renal SLC5A8 also mediates the reabsorption of nicotinate, the ionic form of nicotinic acid (vitamin B3), an essential vitamin for the normal function of all cells (Gopal et al., 2005), and of pyroglutamate, a byproduct of glutathione metabolism (Miyauchi et al., 2010).

Neuronal SLC5A8 contributes to the uptake of lactate and ketone bodies, used as an energy source in the brain under physiological and pathological conditions (Martin et al., 2006). Normally, lactate is the primary metabolic fuel for neurones and derives from the circulation or is generated from glucose by astrocytes. In contrast, ketone bodies are metabolic substrates for neurones during conditions of limited glucose availability such as pregnancy, starvation and uncontrolled diabetes. A similar role for SLC5A8 in the transport of lactate and ketone bodies has been proposed in the retina, in both neurons and retinal epithelial cells (Martin et al., 2007).

The preferred physiological substrate for SLC5A8 in the thyroid gland in unclear. SLC5A8 was first identified on the apical membrane of thyroid follicular cells, and was proposed to contribute to iodide flux into the thyroid lumen for incorporation into thyroglobulin, the precursor of thyroid hormones (Rodriguez et al., 2002). Subsequent studies, however, have shown that SLC5A8 does not transport iodide and SLC5A8 knockout mice have normal thyroid function, leaving the role of SLC5A8 in the thyroid gland an open question (Coady et al., 2004; Miyauchi et al., 2004; Paroder et al., 2006; Frank et al., 2008).

SLC5A8 methylation and silencing in cancer

Independent of its discovery as a solute carrier, SLC5A8 was also identified by Li et al. (2003) as a candidate tumour suppressor gene whose silencing by aberrant methylation is a common and early event in human colon neoplasia. Indeed, epigenetic modifications are a common feature of cancer and are thought to contribute to cancer initiation and progression (Sharma et al., 2010; Hatziapostolou and Iliopoulos, 2011). Epigenetic modifications (DNA methylation, histone acetylation and methylation, chromatin remodelling, and miRNA deregulation) interact with genetic alterations to disrupt gene function. In mammals, methylation of cytosine residues occurs at CpG dinucleotides concentrated in regions of large repetitive sequences, and in CpG islands located in gene promoters. CpG methylation of repetitive elements helps maintain genomic stability, whereas methylation of promoter CpG islands results in transcriptional silencing. In normal differentiated tissues, most CpG sites in the genome are methylated, whereas most gene promoter CpG islands are unmethylated. In contrast, the methylation landscape of the cancer genome is reversed, with global hypomethylation accompanied by hypermethylation of promoter CpG islands. Whereas global DNA hypomethylation increases genomic instability and activates proto-oncogenes, site-specific promoter hypermethylation contributes to tumorigenesis by silencing tumour suppressor genes.

SLC5A8 expression is suppressed in colon cancer, at both the transcriptional and protein level, and this effect is thought to be secondary to SLC5A8 promoter methylation (Li et al., 2003; Dong et al., 2005; Paroder et al., 2006; Thangaraju et al., 2008; Brim et al., 2011). Indeed, the SLC5A8 promoter region is unmethylated in the normal colon mucosa, and is frequently methylated in primary colon cancers, colon adenomas, and aberrant crypt foci (the earliest detectable morphologic abnormality of the colonic epithelium), suggesting that SLC5A8 promoter hypermethylation is an early event in colon tumorigenesis (Li et al., 2003).

Many colon cancer cells lines are also characterized by reduced SLC5A8 expression and promoter hypermethylation (Li et al., 2003). Expression is reactivated following treatment with the demethylating agent 5-azacytidine, confirming that he loss of gene expression is secondary to methylation. SLC5A8 expression is also restored by deletion of DNMT1, suggesting that methylation and therefore silencing is mediated by DNA methyltransferase-1 (Thangaraju et al., 2008).

SLC5A8 promoter methylation and gene silencing has also been demonstrated in various non-colonic neoplasms, including thyroid cancer (Lacroix et al., 2004; Porra et al., 2005; Hu et al., 2006; Schagdarsurengin et al., 2006), breast cancer (Thangaraju et al., 2006), gastric cancer (Ueno et al., 2004), brain cancer (Hong et al., 2005), prostate cancer (Park et al., 2007), pancreatic cancer (Park et al., 2008), head and neck squamous cell carcinoma (Bennett et al., 2008), and acute myeloid leukemia (Whitman et al., 2009). Furthermore, SLC5A8 expression is silenced in several non-colonic cancer cell lines and is restored by demethylating agents, suggesting that methylation-induced silencing of SLC5A8 is a common feature of many types of cancer.

SLC5A8 as a tumour suppressor

A role for SLC5A8 as a tumour suppressor was first suggested by the demonstration that ectopic expression of the gene in SLC5A8-deficient colon cancer cell lines reduces colony formation in vitro, but has no effect on the growth of SLC5A8-proficient cell lines; furthermore, cell lines with restored SLC5A8 expression have a reduced ability to form xenograft tumours in athymic mice (Li et al., 2003). These findings suggest that SLC5A8 methylation and silencing confers a specific growth advantage in the subset of colon cancers in which this locus is inactivated. SLC5A8 over-expression in a head and neck squamous carcinoma cell line also decreases colony growth, suggesting that SLC5A8 is a tumour suppressor at other cancer sites (Bennett et al., 2008).

Role of butyrate: The tumour suppressive function of SLC5A8 in the colon is thought to be secondary to the uptake of SCFAs, particularly butyrate, rather than a direct effect of SLC5A8 itself (Ganapathy et al., 2005; Gupta et al., 2006; Ganapathy et al., 2008). Butyrate is abundant in the colonic lumen (5-15 mM) as a result of bacterial fermentation of undigested organic matter, and is the major metabolic fuel for the colonic epithelium, vital for its normal growth and differentiation in vivo (Roediger, 1982). Butyrate has anticarcinogenic properties and has been shown to inhibit proliferation, and induce differentiation and apoptosis of cancer cells in vitro, including colorectal cancer cells (Kruh, 1982; Tsao et al., 1983; Augeron and Laboisse, 1984; Hague et al., 1993; Heerdt et al., 1994; Hague et al., 1995). Epidemiological studies have long demonstrated the protective effect of dietary fibre against colon cancer (Kim, 2000), and the generation of butyrate by bacterial fermentation is thought underlie this effect.
Butyrate is a known inhibitor of histone deacetylase (HDAC), and as such regulates gene expression through epigenetic mechanisms involving the acetylation status of histones. HDAC inhibitors enhance the acetylation of lysine residues, weakening the interaction between histones and DNA, thereby facilitating transcription. HDAC inhibitors have been shown to cause growth arrest and apoptosis in a variety of tumours (Marks et al., 2001). Thus, the protective effect of dietary fibre against colon cancer is thought to be due, at least partially, to butyrate-mediated HDAC inhibition (Gupta et al., 2006). Other major SCFAs generated in the colon (proprionate and acetate) are less effective than butyrate in terms of HDAC inhibition and in terms of their anti-tumorigenic effects, consistent with the hypothesis that the protective effect of butyrate against colon cancer is related to its ability to inhibit HDAC (Hinnebusch et al., 2002).
The role of SLC5A8 in tumour suppression in the colon by butyrate has been studied in vitro through ectopic expression of SLC5A8 in colon cancer cells in which SLC5A8 is completely silenced. Thus, re-expression of SLC5A8 in SLC5A8-silenced colon cancer cells induces apoptosis, but only when butyrate is present in the culture medium (Thangaraju et al., 2008). Furthermore, HDAC activity is high in SLC5A8-silenced colon cancer cells, and butyrate reduces HDAC activity only following SLC5A8 re-expression. These findings suggest that SLC5A8 per se without its transport function is not a tumour suppressor, but that SLC5A8/butyrate-induced apoptosis in tumour cells involves entry of butyrate into cells via SLC5A8 and subsequent inhibition of HDACs (Ganapathy et al., 2008).
In contrast, animal studies using SLC5A8 knockout mice have failed to confirm the role of SLC5A8/butyrate in colon carcinogenesis. Treatment of SLC5A8 -/- knockout mice with carcinogens and breeding to the APCmin mouse line (which is highly susceptible to spontaneous intestinal adenoma formation) did not reveal a higher incidence of tumour formation, suggesting that SLC5A8 has no apparent role in the prevention of colon tumour formation and growth, at least in this model (Frank et al., 2008). However, butyrate transport by colonic tissues from SLC5A8 knockout mice was not impaired, suggesting that other pathways of butyrate uptake dominate, and may confer protection against tumorigenesis in these animals. Furthermore, butyrate has anti-proliferative and pro-apoptotic effects on a wide variety of cancer cells that do not express SLC5A8, suggesting that butyrate can enter cells and exert an anti-tumorigenic effect independently of SLC5A8.

Role of pyruvate: The expression of SLC5A8 in various normal tissues and its silencing in different cancers raises the possibility that other SLC5A8 substrates may be involved in tumour suppression outside the colon. In an attempt to identify alternative tumour suppressor SLC5A8 substrates, Thangaraju et al. (2006) focused their attention on pyruvate, a ubiquitous metabolite present in the circulation at concentrations of 100 uM, and a normal supplement of cell culture media. SLC5A8 is silenced in MCF-7 breast carcinoma cells through methylation. Ectopic expression of SLC5A8 in MCF-7 cells and exposure to pyruvate induces apoptosis and inhibits colony formation; in contrast, exposure of such cells to lactate, another SLC5A8 substrate, has no effect (Thangaraju et al., 2006). The apoptotic response of SLC5A8-expressing MCF-7 cells to pyruvate is accompanied by up-regulation of proapoptotic factors (p53, Bax, Bak, TRAIL, TRAILR1, and TRAILR2) and down-regulation of antiapoptotic factors (Bcl2, Bcl-W, and survivin), whereas, the expression of apoptosis-related genes is not affected by lactate. Pyruvate, but not lactate, inhibits HDAC activity with a similar potency as butyrate, supporting the hypothesis that tumour suppression by SLC5A8 is due to the uptake of substrates such as pyruvate that alter the expression of apoptosis-related genes by modifying the acetylation status of histones (Thangaraju et al., 2006).

Clinical and therapeutic implications

SLC5A8 expression correlates with survival in colon cancer suggesting a clinical utility as prognostic marker (Paroder et al., 2006). SLC5A8 protein expression is significantly reduced or absent in Duke C (locally advanced lymph-node-positive) colorectal cancer, irrespective of the differentiation status of tumours. Patients with low SLC5A8-expressing tumours show shorter disease-free and overall survival compared with patients with higher SLC5A8 expression, suggesting that SLC5A8 expression is a favourable indicator of colorectal cancer prognosis (Paroder et al., 2006).

The silencing of SLC5A8 at cancer sites, and the important role of this transporter in the uptake of monocarboxylates with HDAC inhibitory activity, suggests that SLC5A8 may represent a strategic target for the treatment of cancer. A recent study has demonstrated that actividin A, a member of the TGF-β superfamily, induces SLC5A8 expression in human colon cancer cells by activating transcription through the Smad3 signalling pathway, and suppresses colony formation (Zhang et al., 2010). Thus, drugs that activate Smad signalling may represent a novel means of restoring the tumour suppressor function of SLC5A8 in cancers subject to SLC5A8 silencing. Since HDAC inhibitors themselves are candidate drugs in cancer therapy, re-expression of SLC5A8 in tumour cells may improve the effectiveness of SLC5A8-transported HDAC inhibitors.

 

Bibliography

Effects of sodium butyrate, a new pharmacological agent, on cells in culture.
Kruh J.
Mol Cell Biochem. 1982 Feb 5;42(2):65-82. (REVIEW)
PMID 6174854
 
Utilization of nutrients by isolated epithelial cells of the rat colon.
Roediger WE.
Gastroenterology. 1982 Aug;83(2):424-9.
PMID 7084619
 
Effect of sodium butyrate on carcinoembryonic antigen production by human colonic adenocarcinoma cells in culture.
Tsao D, Shi ZR, Wong A, Kim YS.
Cancer Res. 1983 Mar;43(3):1217-22.
PMID 6825092
 
Emergence of permanently differentiated cell clones in a human colonic cancer cell line in culture after treatment with sodium butyrate.
Augeron C, Laboisse CL.
Cancer Res. 1984 Sep;44(9):3961-9.
PMID 6744312
 
Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53-independent pathway: implications for the possible role of dietary fibre in the prevention of large-bowel cancer.
Hague A, Manning AM, Hanlon KA, Huschtscha LI, Hart D, Paraskeva C.
Int J Cancer. 1993 Sep 30;55(3):498-505.
PMID 8397167
 
Potentiation by specific short-chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines.
Heerdt BG, Houston MA, Augenlicht LH.
Cancer Res. 1994 Jun 15;54(12):3288-93.
PMID 8205551
 
Apoptosis in colorectal tumour cells: induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate.
Hague A, Elder DJ, Hicks DJ, Paraskeva C.
Int J Cancer. 1995 Jan 27;60(3):400-6.
PMID 7829251
 
AGA technical review: impact of dietary fiber on colon cancer occurrence.
Kim YI.
Gastroenterology. 2000 Jun;118(6):1235-57. (REVIEW)
PMID 10833499
 
Histone deacetylases and cancer: causes and therapies.
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK.
Nat Rev Cancer. 2001 Dec;1(3):194-202. (REVIEW)
PMID 11902574
 
Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides.
Topping DL, Clifton PM.
Physiol Rev. 2001 Jul;81(3):1031-64. (REVIEW)
PMID 11427691
 
The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation.
Hinnebusch BF, Meng S, Wu JT, Archer SY, Hodin RA.
J Nutr. 2002 May;132(5):1012-7.
PMID 11983830
 
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
 
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. Epub 2003 Jun 26.
PMID 12829793
 
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. Epub 2004 Apr 16.
PMID 15090606
 
Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate.
Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin P, Smith SB, Prasad PD, Ganapathy V.
J Biol Chem. 2004 Oct 22;279(43):44522-32. Epub 2004 Aug 17.
PMID 15322102
 
Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters.
Lacroix L, Pourcher T, Magnon C, Bellon N, Talbot M, Intaraphairot T, Caillou B, Schlumberger M, Bidart JM.
J Clin Endocrinol Metab. 2004 Mar;89(3):1423-8.
PMID 15001644
 
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. Epub 2004 Feb 13.
PMID 14966140
 
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
 
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
 
Biological functions of SLC5A8, a candidate tumour suppressor.
Ganapathy V, Gopal E, Miyauchi S, Prasad PD.
Biochem Soc Trans. 2005 Feb;33(Pt 1):237-40. (REVIEW)
PMID 15667316
 
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
 
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
 
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. Epub 2005 Feb 1.
PMID 15687339
 
Histochemical demonstration of a Na(+)-coupled transporter for short-chain fatty acids (slc5a8) in the intestine and kidney of the mouse.
Takebe K, Nio J, Morimatsu M, Karaki S, Kuwahara A, Kato I, Iwanaga T.
Biomed Res. 2005 Oct;26(5):213-21.
PMID 16295698
 
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. Epub 2005 Dec 20. (REVIEW)
PMID 16375929
 
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
 
Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8.
Iwanaga T, Takebe K, Kato I, Karaki S, Kuwahara A.
Biomed Res. 2006 Oct;27(5):243-54.
PMID 17099289
 
Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain.
Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, Smith SB, Prasad PD, Ganapathy V.
J Neurochem. 2006 Jul;98(1):279-88.
PMID 16805814
 
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. Epub 2006 May 2.
PMID 16670197
 
CpG island methylation of tumor-related promoters occurs preferentially in undifferentiated carcinoma.
Schagdarsurengin U, Gimm O, Dralle H, Hoang-Vu C, Dammann R.
Thyroid. 2006 Jul;16(7):633-42.
PMID 16889486
 
SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases.
Thangaraju M, Gopal E, Martin PM, Ananth S, Smith SB, Prasad PD, Sterneck E, Ganapathy V.
Cancer Res. 2006 Dec 15;66(24):11560-4.
PMID 17178845
 
Colonic health: fermentation and short chain fatty acids.
Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ.
J Clin Gastroenterol. 2006 Mar;40(3):235-43. (REVIEW)
PMID 16633129
 
Establishing a definitive stoichiometry for the Na+/monocarboxylate cotransporter SMCT1.
Coady MJ, Wallendorff B, Bourgeois F, Charron F, Lapointe JY.
Biophys J. 2007 Oct 1;93(7):2325-31. Epub 2007 May 25.
PMID 17526579
 
Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract.
Gopal E, Miyauchi S, Martin PM, Ananth S, Roon P, Smith SB, Ganapathy V.
Pharm Res. 2007 Mar;24(3):575-84.
PMID 17245649
 
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
 
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. Epub 2007 Nov 26.
PMID 18037591
 
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
 
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. Epub 2008 Jun 17.
PMID 18562324
 
Sodium-coupled monocarboxylate transporters in normal tissues and in cancer.
Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD.
AAPS J. 2008;10(1):193-9. Epub 2008 Apr 2. (REVIEW)
PMID 18446519
 
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
 
Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer.
Thangaraju M, Cresci G, Itagaki S, Mellinger J, Browning DD, Berger FG, Prasad PD, Ganapathy V.
J Gastrointest Surg. 2008 Oct;12(10):1773-81; discussion 1781-2. Epub 2008 Jul 26.
PMID 18661192
 
DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication.
Whitman SP, Hackanson B, Liyanarachchi S, Liu S, Rush LJ, Maharry K, Margeson D, Davuluri R, Wen J, Witte T, Yu L, Liu C, Bloomfield CD, Marcucci G, Plass C, Caligiuri MA.
Blood. 2008 Sep 1;112(5):2013-6. Epub 2008 Jun 19.
PMID 18566324
 
Sodium-coupled electrogenic transport of pyroglutamate (5-oxoproline) via SLC5A8, a monocarboxylate transporter.
Miyauchi S, Gopal E, Babu E, Srinivas SR, Kubo Y, Umapathy NS, Thakkar SV, Ganapathy V, Prasad PD.
Biochim Biophys Acta. 2010 Jun;1798(6):1164-71. Epub 2010 Mar 6.
PMID 20211600
 
Epigenetics in cancer.
Sharma S, Kelly TK, Jones PA.
Carcinogenesis. 2010 Jan;31(1):27-36. Epub 2009 Sep 13. (REVIEW)
PMID 19752007
 
Activin A induces SLC5A8 expression through the Smad3 signaling pathway in human colon cancer RKO cells.
Zhang Y, Bao YL, Yang MT, Wu Y, Yu CL, Huang YX, Sun Y, Zheng LH, Li YX.
Int J Biochem Cell Biol. 2010 Dec;42(12):1964-72. Epub 2010 Aug 21.
PMID 20732443
 
SLC5A8 gene, a transporter of butyrate: a gut flora metabolite, is frequently methylated in African American colon adenomas.
Brim H, Kumar K, Nazarian J, Hathout Y, Jafarian A, Lee E, Green W, Smoot D, Park J, Nouraie M, Ashktorab H.
PLoS One. 2011;6(6):e20216. Epub 2011 Jun 8.
PMID 21687703
 
Epigenetic aberrations during oncogenesis.
Hatziapostolou M, Iliopoulos D.
Cell Mol Life Sci. 2011 May;68(10):1681-702. Epub 2011 Jan 20. (REVIEW)
PMID 21249513
 
Written2011-12Kerry J Rhoden
Genetics Unit, Department of Gynecologic, Obstetric, Pediatric Sciences, University of Bologna, Policlinico S Orsola-Malpighi, via Massarenti 9, Bologna 40138, Italy

Citation

This paper should be referenced as such :
Rhoden, KJ
SLC5A8, its role in tumorigenesis
Atlas Genet Cytogenet Oncol Haematol. 2012;16(6):436-440.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Deep/SLC5A8inCancerID20107.htm

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Mar 14 13:58:12 CET 2017


Home   Genes    Leukemias    Solid Tumours    Cancer-Prone    Deep Insight    Case Reports    Journals   Portal    Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.