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Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3

Human organic cation transporter 3 (OCT3, SLC22A3) mediates the uptake of many important endogenous amines and basic drugs in a variety of tissues. OCT3 is identified as one of the important risk loci for prostate cancer and is markedly under-expressed in aggressive prostate cancers. The goal of thi...

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Autores principales: Chen, Ligong, Hong, Chibo, Chen, Eugene C., Yee, Sook Wah, Xu, Lu, Almof, Emil U., Wen, Christopher, Fujii, Kacyn, Johns, Susan J., Stryke, Doug, Ferrin, Thomas E., Simko, Jeff, Chen, Xin, Costello, Joseph F., Giacomini, Kathleen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396779/
https://www.ncbi.nlm.nih.gov/pubmed/22231567
http://dx.doi.org/10.1038/tpj.2011.60
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author Chen, Ligong
Hong, Chibo
Chen, Eugene C.
Yee, Sook Wah
Xu, Lu
Almof, Emil U.
Wen, Christopher
Fujii, Kacyn
Johns, Susan J.
Stryke, Doug
Ferrin, Thomas E.
Simko, Jeff
Chen, Xin
Costello, Joseph F.
Giacomini, Kathleen M.
author_facet Chen, Ligong
Hong, Chibo
Chen, Eugene C.
Yee, Sook Wah
Xu, Lu
Almof, Emil U.
Wen, Christopher
Fujii, Kacyn
Johns, Susan J.
Stryke, Doug
Ferrin, Thomas E.
Simko, Jeff
Chen, Xin
Costello, Joseph F.
Giacomini, Kathleen M.
author_sort Chen, Ligong
collection PubMed
description Human organic cation transporter 3 (OCT3, SLC22A3) mediates the uptake of many important endogenous amines and basic drugs in a variety of tissues. OCT3 is identified as one of the important risk loci for prostate cancer and is markedly under-expressed in aggressive prostate cancers. The goal of this study was to identify genetic and epigenetic factors in the promoter region that influence the expression level of OCT3. Haplotypes that contained the common variants, g.-81G>delGA (rs60515630) (minor allele frequency (MAF) 11.5% in African American) and g.-2G>A (rs555754) (MAF>30% in all ethnic groups) showed significant increases in luciferase reporter activities and exhibited stronger transcription factor binding affinity than the haplotypes that contained the major alleles. Consistent with the reporter assays, OCT3 mRNA expression levels were significantly higher in Asian (P<0.001) and Caucasian (P<0.05) liver samples from individuals who were homozygous for g.-2A/A in comparison with those homozygous for the g.-2G/G allele. Studies revealed that the methylation level in the basal promoter region of OCT3 was associated with OCT3 expression level and tumorigenesis capability in various prostate cancer cell lines. The methylation level of the OCT3 promoter was higher in 62% of prostate tumor samples compared with matched normal samples. Our studies demonstrate that genetic polymorphisms in the proximal promoter region of OCT3 alter the transcription rate of the gene and may be associated with altered expression levels of OCT3 in human liver. Aberrant methylation contributes to the reduced expression of OCT3 in prostate cancer.
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spelling pubmed-33967792013-10-01 Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3 Chen, Ligong Hong, Chibo Chen, Eugene C. Yee, Sook Wah Xu, Lu Almof, Emil U. Wen, Christopher Fujii, Kacyn Johns, Susan J. Stryke, Doug Ferrin, Thomas E. Simko, Jeff Chen, Xin Costello, Joseph F. Giacomini, Kathleen M. Pharmacogenomics J Article Human organic cation transporter 3 (OCT3, SLC22A3) mediates the uptake of many important endogenous amines and basic drugs in a variety of tissues. OCT3 is identified as one of the important risk loci for prostate cancer and is markedly under-expressed in aggressive prostate cancers. The goal of this study was to identify genetic and epigenetic factors in the promoter region that influence the expression level of OCT3. Haplotypes that contained the common variants, g.-81G>delGA (rs60515630) (minor allele frequency (MAF) 11.5% in African American) and g.-2G>A (rs555754) (MAF>30% in all ethnic groups) showed significant increases in luciferase reporter activities and exhibited stronger transcription factor binding affinity than the haplotypes that contained the major alleles. Consistent with the reporter assays, OCT3 mRNA expression levels were significantly higher in Asian (P<0.001) and Caucasian (P<0.05) liver samples from individuals who were homozygous for g.-2A/A in comparison with those homozygous for the g.-2G/G allele. Studies revealed that the methylation level in the basal promoter region of OCT3 was associated with OCT3 expression level and tumorigenesis capability in various prostate cancer cell lines. The methylation level of the OCT3 promoter was higher in 62% of prostate tumor samples compared with matched normal samples. Our studies demonstrate that genetic polymorphisms in the proximal promoter region of OCT3 alter the transcription rate of the gene and may be associated with altered expression levels of OCT3 in human liver. Aberrant methylation contributes to the reduced expression of OCT3 in prostate cancer. 2012-01-10 2013-04 /pmc/articles/PMC3396779/ /pubmed/22231567 http://dx.doi.org/10.1038/tpj.2011.60 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Chen, Ligong
Hong, Chibo
Chen, Eugene C.
Yee, Sook Wah
Xu, Lu
Almof, Emil U.
Wen, Christopher
Fujii, Kacyn
Johns, Susan J.
Stryke, Doug
Ferrin, Thomas E.
Simko, Jeff
Chen, Xin
Costello, Joseph F.
Giacomini, Kathleen M.
Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3
title Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3
title_full Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3
title_fullStr Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3
title_full_unstemmed Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3
title_short Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3
title_sort genetic and epigenetic regulation of the organic cation transporter 3, slc22a3
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396779/
https://www.ncbi.nlm.nih.gov/pubmed/22231567
http://dx.doi.org/10.1038/tpj.2011.60
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