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Li, Markowitz
SMCT / SLC5A8 transporters
Romero Labs
2004
"Last year, Dr. Hui Li in Dr. Sandy Markowitz's lab, discovered a novel tumor suppressor for colon cancer. When the promoter is methylated the gene is INactivated and results in colon cancer .... 100% of the time. Methylation mediated inactivation of this gene accounts for ~60% of all known colon cancers (Li et al., PNAS, 100: 8412-8417, 2003). This tumor suppressor gene is a transporter protein in the SLC5, aka, Na - glucose cotransporter family and was named SLC5A8. The SLC5A8 mRNA is found in kidney and colon.
"Recently, in collaboration with Drs. Mike Coady and Jean-Yves Lapointe (U. Montreal), we discovered that SLC5A8 functions as a Na+ coupled monocarboxylate cotransporter (SMCT). We are continuing to work on the biophysics of SMCT to understand why its inactivation leads to colon cancer."
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.
"We identify a gene, SLC5A8, and show it is a candidate tumor suppressor gene whose silencing by aberrant methylation is a common and early event in human colon neoplasia. Aberrant DNA methylation has been implicated as a component of an epigenetic mechanism that silences genes in human cancers. Using restriction landmark genome scanning, we performed a global search to identify genes that would be aberrantly methylated at high frequency in human colon cancer. From among 1,231 genomic NotI sites assayed, site 3D41 was identified as methylated in 11 of 12 colon cancers profiled. Site 3D41 mapped to exon 1 of SLC5A8, a transcript that we assembled. In normal colon mucosa we found that SLC5A8 exon 1 is unmethylated and SLC5A8 transcript is expressed. In contrast, SLC5A8 exon 1 proved to be aberrantly methylated in 59% of primary colon cancers and 52% of colon cancer cell lines. SLC5A8 exon 1 methylated cells were uniformly silenced for SLC5A8 expression, but reactivated expression on treatment with a demethylating drug, 5-azacytidine. 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. SLC5A8 exon 1 methylation is an early event, detectable in colon adenomas, and in even earlier microscopic colonic aberrant crypt foci. 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."