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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 (KJR)
Published in Atlas Database: December 2011
Online updated version : http://AtlasGeneticsOncology.org/Deep/SLC5A8inCancerID20107.html
DOI: 10.4267/2042/47346
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© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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
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 sodiumcoupled 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).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
436
SLC5A8 and its role in tumorigenesis
Rhoden KJ
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, sitespecific 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 methylationinduced silencing of SLC5A8 is a common feature of
many types of cancer.
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
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
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
437
SLC5A8 and its role in tumorigenesis
Rhoden KJ
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 proapoptotic 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 SLC5A8expressing MCF-7 cells to pyruvate is accompanied by
up-regulation of proapoptotic factors (p53, Bax, Bak,
TRAIL, TRAILR1, and TRAILR2) and downregulation 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).
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 SLC5A8silenced 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
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
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,
438
SLC5A8 and its role in tumorigenesis
Rhoden KJ
Hinnebusch BF, Meng S, Wu JT, Archer SY, Hodin RA. The
effects of short-chain fatty acids on human colon cancer cell
phenotype are associated with histone hyperacetylation. J
Nutr. 2002 May;132(5):1012-7
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.
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