Disease relevance of SLC5A8

• Structural homology and functional testing demonstrated that SLC5A8 is a member of the family of sodium solute symporters, which are now added as a class of candidate colon cancer suppressor genes [1].
• SLC5A8 exon 1 methylation is an early event, detectable in colon adenomas, and in even earlier microscopic colonic aberrant crypt foci [1].
• Expression of exogenous SLC5A8 in LN229 and LN443 glioma cells inhibited colony formation, suggesting that it may function as a growth suppressor in normal brain cells [2].
• Using an integrated approach for genome-wide methylation and copy number analyses, we identified SLC5A8 on chromosome 12q23.1 that was affected frequently by aberrant methylation in human astrocytomas and oligodendrogliomas [2].
• In thyroid carcinomas, the mean and median hAIT mRNA levels were significantly decreased [3].

High impact information on SLC5A8

• Mechanisms of thrombocytopenia were studied in 38 patients with mild to moderately severe chronic autoimmune thrombocytopenia (AITP) [4].
• In summary, both depressed platelet production and increased platelet clearance by the liver and spleen contribute to the thrombocytopenia of AITP [4].
• Peripheral blood lymphocytes from 38 patients with autoimmune thrombocytopenic purpura (AITP) were tested for HLA-A, -B, and -C alloantigens [5].
• These data indicate that a predisposition to AITP is inherited with a DRw2 gene of the major histocompatibility system [5].
• 122 adults with severe AITP (platelet count < or =20 x 10(9)/L) were randomly assigned to receive either intravenous immunoglobulin or high-dose methylprednisolone on days 1-3 (randomisation A), and then to receive either oral prednisone or placebo (randomisation B) on days 4-21 [6].

Chemical compound and disease context of SLC5A8

• When MCF7 breast tumor cells are transfected with SLC5A8 cDNA, the cells undergo pyruvate-dependent apoptosis [7].
• Previous studies of the immune response in polytransfused Glanzmann thrombasthenia (GT) patients and in autoimmune thrombocytopenic purpura (AITP) have relied on serum analysis and have shown the frequent development of Abs directed against the alpha(IIb)beta(3) integrin [8].
• In chronic immune thrombocytopenic purpura (AITP), autoantibodies directed mainly against platelet membrane glycoprotein (GP) IIb/IIIa cause platelet destruction by Fc-mediated phagocytosis or by complement lysis [9].
• Sixty-six adults with chronic autoimmune thrombocytopenic purpura AITP and platelet count <50 x 10(9)/l were treated with dapsone (75-100 mg orally) [10].
• A 46-year-old white male with small cell lung cancer (SCLC) limited to the thorax developed autoimmune thrombocytopenic purpura (AITP), following a cyclophosphamide, paclitaxel and G-CSF-containing regimen for peripheral blood stem cell (PBSC) mobilization [11].

Biological context of SLC5A8

• SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers [1].
• Transfection of SLC5A8 suppressed colony growth in each of three SLC5A8-deficient cell lines, but showed no suppressive effect in any of three SLC5A8-proficient cell lines [1].
• The differential ability of these monocarboxylates to cause apoptosis in SLC5A8-expressing MCF7 cells correlates with their ability to inhibit HDACs [7].
• We found that SLC5A8 is expressed in nontransformed breast epithelial cell lines but silenced by DNA methylation in tumor cell lines [7].
• We propose that tumor cells silence SLC5A8 and convert pyruvate into lactate as complementary mechanisms to avoid pyruvate-induced cell death [7].

Anatomical context of SLC5A8

• In contrast, SLC5A8 exon 1 proved to be aberrantly methylated in 59% of primary colon cancers and 52% of colon cancer cell lines [1].
• In normal colon mucosa we found that SLC5A8 exon 1 is unmethylated and SLC5A8 transcript is expressed [1].
• Exposure of SLC5A8-expressing oocytes to these fatty acids induced inward currents under voltage-clamp conditions in a Na(+)-dependent manner [12].
• In the present report, we analyzed both hAIT gene and protein expressions in a large series of benign and malignant human thyroid tissues [3].
• The ability of SLC5A8 to deliver butyrate into colonic epithelial cells most likely underlies the tumor suppressive role of this transporter [13].

Associations of SLC5A8 with chemical compounds

• SLC5A8 exon 1 methylated cells were uniformly silenced for SLC5A8 expression, but reactivated expression on treatment with a demethylating drug, 5-azacytidine [1].
• Uptake of short-chain fatty acids (lactate, pyruvate, acetate, propionate, and butyrate) in oocytes expressing SLC5A8 was severalfold higher than in uninjected oocytes [12].
• Recently, we identified a human gene and its protein product, designated hAIT, as a putative new transporter involved in iodide transfer across the apical membrane of thyrocytes [3].
• SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases [7].
• Butyrate and propionate also induce apoptosis in SLC5A8-expressing cells, whereas lactate does not [7].

Physical interactions of SLC5A8

• Silencing of SLC5A8 coupled with conversion of pyruvate into lactate in tumor cells correlates with increased HDAC activity in these cells compared with nontransformed cells [7].

Regulatory relationships of SLC5A8

• The BRAF activating mutation and hypermethylation of SLC5A8, which mediates short chain fatty acid transport, may be the important events in the genesis of SSAs [14].

Other interactions of SLC5A8

• SLC5A8, a tumor suppressor gene down-regulated in human colon cancer, codes for a transporter in the Na(+)/glucose cotransporter gene family, but the definitive functional identity of the transporter protein is not known [12].
• It was designated hAIT for human Apical Iodide Transporter [15].
• Here, we show that pyruvate, but not lactate, is an inhibitor of histone deacetylases (HDAC) and an inducer of apoptosis in tumor cells and that SLC5A8, a Na(+)/monocarboxylate cotransporter, is obligatory for this process [7].
• Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas [16].
• Interaction of ibuprofen and other structurally related NSAIDs with the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8) [17].

Analytical, diagnostic and therapeutic context of SLC5A8

• Using immunohistochemistry, hAIT staining was detected in normal thyroid tissue in about 10% of follicles; in positive follicles, 10-40% of thyrocytes, mostly the tall cells, were stained [3].
• SLC5A8 expression was selectively down-regulated (40-fold) in papillary thyroid carcinomas of classical form (PTC-cf.). Methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of PTC-cf. and in about 20% of other papillary thyroid carcinomas [16].
• In addition, chromatin immunoprecipitation assays showed that acetylation of histone H3 in the 5' region of the gene correlated directly with SLC5A8 expression and inversely with DNA methylation [18].
• Moreover, repeated i.v. IgG reinfusion could be an alternative for AITP patients in whom splenectomy is contraindicated [19].
• In 42 patients with autoimmune thrombocytopenia (AITP) and a positive direct platelet suspension immunofluorescence test (PSIFT), the antigenic specificity of the autoantibodies was studied [20].

References