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

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Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3 The Pharmacogenomics Journal (2013) 13, 110–120 & 2013 Macmillan Publishers Limited. All rights reserved 1470-269X/13 www.nature.com/tpj ORIGINAL ARTICLE Genetic and epigenetic regulation of the organic cation transporter 3, SLC22A3 L Chen1, C Hong2, EC Chen1, Human organic cation transporter 3 (OCT3 and SLC22A3) mediates the 1 1 1 uptake of many important endogenous amines and basic drugs in a variety of SW Yee ,LXu, EU Almof , tissues. OCT3 is identified as one of the important risk loci for prostate cancer, 1 1 3 C Wen , K Fujii , SJ Johns , and is markedly underexpressed in aggressive prostate cancers. The goal D Stryke3, TE Ferrin3, J Simko4, of this study was to identify genetic and epigenetic factors in the promoter X Chen1, JF Costello2 and region that influence the expression level of OCT3. Haplotypes that 1 contained the common variants, g.À81G4delGA (rs60515630) (minor KM Giacomini allele frequency 11.5% in African American) and g.À2G4A (rs555754) 1Department of Bioengineering and Therapeutic (minor allele frequency430% in all ethnic groups) showed significant Sciences, University of California San Francisco, increases in luciferase reporter activities and exhibited stronger transcription San Francisco, CA, USA; 2Department of factor-binding affinity than the haplotypes that contained the major alleles. Neurological Surgery, University of California San Consistent with the reporter assays, OCT3 messenger RNA expression levels Francisco, San Francisco, CA, USA; 3Department of Pharmaceutical Chemistry, University of were significantly higher in Asian (Po0.001) and Caucasian (Po0.05) liver California San Francisco, San Francisco, CA, USA samples from individuals who were homozygous for g.À2A/A in comparison and 4Department of Pathology and Urology, with those homozygous for the g.À2G/G allele. Studies revealed that the University of California San Francisco, San methylation level in the basal promoter region of OCT3 was associated with Francisco, CA, USA OCT3 expression level and tumorigenesis capability in various prostate cancer Correspondence: cell lines. The methylation level of the OCT3 promoter was higher in 62% of Professor KM Giacomini, Department of prostate tumor samples compared with matched normal samples. Our Bioengineering and Therapeutic Sciences, studies demonstrate that genetic polymorphisms in the proximal promoter University of California at San Francisco, 1550 region of OCT3 alter the transcription rate of the gene and may be associated 4th Street, San Francisco, CA 94158, USA. E-mail: [email protected] with altered expression levels of OCT3 in human liver. Aberrant methylation contributes to the reduced expression of OCT3 in prostate cancer. The Pharmacogenomics Journal (2013) 13, 110–120; doi:10.1038/tpj.2011.60; published online 10 January 2012 Keywords: methylation; polymorphism; prostate cancer; SLC22A3 Introduction The organic cation transporter 3, OCT3 (SLC22A3) is increasingly being recognized as an important modulator of human disease and drug response. Recent genome-wide association studies have linked OCT3 to risk loci for prostate cancer, colorectal cancer as well as for other diseases.1–6 In prostate cancer, OCT3, which is markedly underexpressed in high Gleason-grade tumors, has been found to be among the lowest expressed genes; in addition, OCT3 expression is associated with progression of prostate cancer.4,5 For example, studies have suggested that OCT3 may serve as an important biomarker for Gleason grade.4,5 As it transports many important monoamines including serotonin, histamine and norepinephrine,7–10 OCT3 appears to have a pleio- tropic role in human physiology and pathophysiology. Received 15 June 2011; revised 4 October 2011; accepted 7 November 2011; Although the expression of its paralogs, OCT1 (SLC22A1) and OCT2 published online 10 January 2012 (SLC22A2), is restricted mainly to excretory organs such as the liver and kidney, Promoter methylation and polymorphism of SLC22A3 L Chen et al 111 OCT3 (SLC22A3) exhibits a much broader tissue distribu- of California at San Francisco. The Gleason grade of the tion.7,8,11 Expressed in heart, brain, liver, skeletal muscle, prostate cancer tissue varies from 6 to 7 as examined by the prostate and placenta, OCT3 has a role in the disposition of a Center. Normal Caucasian liver samples were purchased variety of cationic substances including endogenous amines from Asterand (Detroit, MI, USA) and Capital Biosciences and therapeutic and illicit drugs.7,11–13 Important single (Rockville, MD, USA). The age of the donors of the liver nucleotide polymorphisms (SNPs) of OCT3 have been samples ranges from 36 to 83 years. All the Asian tumor and identified and associated with its messenger RNA (mRNA) non-tumor liver samples were collected from liver resections level or risk for prostate cancer, colorectal cancer, coronary at the University of Hong Kong. The age of the Asian donors artery disease and other human disease.1–3,6,11,14,15 Though for liver tissues ranges from 38 to 82 years. All samples were several recent studies have investigated the effects of obtained with informed consent, and the usage was promoter region variants in transporter genes on transcrip- approved by both the Committee on Human Research at tion rates, gene expression and drug response,16–19 there has the University of California at San Francisco and the Ethics been no systematic examination of the genetic variants in Committee of the University of Hong Kong. Information the promoter region of OCT3. concerning the tissue donors is listed in the Supplementary Epigenetic gene silencing through DNA methylation is Table S2. For determination of OCT3 expression levels, we one of the important steps in tumorigenesis.20–26 Of the used 40 samples from Asians and 29 from Caucasians. In various epigenetic modifications, hypermethylation of methylation studies, 12 liver samples and 16 prostate the promoter regions of tumor suppressor genes, which samples were used. Five and seven cell lines were used for represses transcription, has been most extensively stu- luciferase assay and methylation studies, respectively. All died.21,22,27 DNA methylation has a central role in the the cell lines were purchased from American Type Culture tissue-specific expression of transporters and regulates the Collection and (Manassas, VA, USA) validated by the expression of certain transporters in cancer cell lines.28–32 University of California San Fransisco Cell Culture Facility. OCT3 shows significantly lower expression levels in several types of cancers, especially in high Gleason-grade prostate Genetic analysis cancer.4,5,13 However, the mechanisms responsible for the Genomic DNA samples were collected from unrelated reduced expression levels of OCT3 are not understood. The healthy individuals from four major ethnic groups (68 each basal promoter of OCT3 is located within a large CpG island from European Americans, African Americans, Chinese extending into exon 1 (Supplementary Figure S1); aberrant Americans, and Mexican Americans) as a part of the Study methylation of this region could reduce the expression of Of PHarmacogenetics In Ethnically Diverse Populations OCT3. (SOPHIE). To identify polymorphisms in the promoter In this investigation, we examined polymorphisms in the region of OCT3, a PCR fragment (À706 to þ 223 bp from basal promoter region of OCT3 using data from direct the translational start site) was amplified and directly sequencing of a large DNA sample set (n ¼ 272) from four sequenced by an automated genetic analyzer using the racial/ethnic populations to identify OCT3 variants. The primers listed in Supplementary Table S1.17 OCT3 genetic functional significance of OCT3 promoter variants in variants and their frequencies are listed in Table 1a. luciferase reporter assays was assessed. Further, several Haplotype assembly was performed using the Haploview prostate cancer cell lines and primary cancer tissues were 4.1 program (Broad Institute, Cambridge, MA, USA), based screened to determine whether methylation in the OCT3 on a standard expectation–maximization algorithm, to promoter region results in the underexpression of OCT3 in reconstruct individual haplotypes from population geno- prostate cancer. Our results demonstrate that a common type data. The haplotypes and their frequencies are listed in variant g.À2G4A (rs555754) increases the transcription of Table 1b. Nucleotide location number was assigned from the OCT3 in luciferase reporter assays and is associated with translational start site according to the OCT3 mRNA high expression levels of OCT3 in primary human liver sequence (GenBank accession number: NM_021977.2). For tissues. In addition, our results show that epigenetic genotyping the liver samples from Caucasian and Asian silencing in the OCT3 promoter region is an important donors, the same primers for cloning the OCT3 with mechanism to suppress the expression of OCT3 in several luciferase (Supplementary Table S1) were used to amplify prostate cancer cell lines and tissues. These observations the PCR products. The PCR products were processed with strongly suggest that both genetic and epigenetic factors ExoSAP-IT (Affymetrix, Santa Clara, CA, USA) for clean-up critically mediate the expression level of OCT3, and may be and then were directly sequenced with the forward primer. important in tumorigenesis and drug responses. Construction of various reporter plasmids containing OCT3 promoter region variants Materials and methods To construct the reporter
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  • Supplementary Table 1
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