SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers

Hui Li, Lois Myeroff, Dominic Smiraglia, Michael F. Romero, Theresa P. Pretlow, Lakshmi Kasturi, James Lutterbaugh, Ronald M. Rerko, Graham Casey, Jean Pierre Issa, Joseph Willis, James K V Willson, Christoph Plass, Sanford D. Markowitz

Research output: Contribution to journalArticle

219 Citations (Scopus)

Abstract

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 Notl 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.

Original languageEnglish (US)
Pages (from-to)8412-8417
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number14
DOIs
StatePublished - Jul 8 2003

Fingerprint

Aberrant Crypt Foci
Tumor Suppressor Genes
Colonic Neoplasms
Methylation
Colon
Sodium
Exons
Neoplasms
Cell Line
Genes
Symporters
Azacitidine
Gene Silencing
DNA Methylation
Epigenomics
Adenoma
Transfection
Mucous Membrane
Genome
Growth

Keywords

  • Colon cancer

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. / Li, Hui; Myeroff, Lois; Smiraglia, Dominic; Romero, Michael F.; Pretlow, Theresa P.; Kasturi, Lakshmi; Lutterbaugh, James; Rerko, Ronald M.; Casey, Graham; Issa, Jean Pierre; Willis, Joseph; Willson, James K V; Plass, Christoph; Markowitz, Sanford D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 14, 08.07.2003, p. 8412-8417.

Research output: Contribution to journalArticle

Li, H, Myeroff, L, Smiraglia, D, Romero, MF, Pretlow, TP, Kasturi, L, Lutterbaugh, J, Rerko, RM, Casey, G, Issa, JP, Willis, J, Willson, JKV, Plass, C & Markowitz, SD 2003, 'SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8412-8417. https://doi.org/10.1073/pnas.1430846100
Li, Hui ; Myeroff, Lois ; Smiraglia, Dominic ; Romero, Michael F. ; Pretlow, Theresa P. ; Kasturi, Lakshmi ; Lutterbaugh, James ; Rerko, Ronald M. ; Casey, Graham ; Issa, Jean Pierre ; Willis, Joseph ; Willson, James K V ; Plass, Christoph ; Markowitz, Sanford D. / SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 14. pp. 8412-8417.
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T1 - SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers

AU - Li, Hui

AU - Myeroff, Lois

AU - Smiraglia, Dominic

AU - Romero, Michael F.

AU - Pretlow, Theresa P.

AU - Kasturi, Lakshmi

AU - Lutterbaugh, James

AU - Rerko, Ronald M.

AU - Casey, Graham

AU - Issa, Jean Pierre

AU - Willis, Joseph

AU - Willson, James K V

AU - Plass, Christoph

AU - Markowitz, Sanford D.

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N2 - 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 Notl 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.

AB - 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 Notl 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.

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