Abstract
Aberrant methylation of promoter CpG islands (CGI) is involved in silencing of tumor suppressor genes and is also a potential cancer biomarker. Here, to identify CGIs aberrantly methylated in human melanomas, we did a genome-wide search using methylation-sensitive representational difference analysis. CGIs in putative promoter regions of 34 genes (ABHD9, BARHL1, CLIC5, CNNM1, COL2A1, CPT1C, DDIT4L, DERL3, DHRS3, DPYS, EFEMP2, FAM62C, FAM78A, FLJ33790, GBX2, GPR10, GPRASP1, HOXA9, HOXD11, HOXD12, HOXD13, p14ARF, PAX6, PRDX2, PTPRG, RASD1, RAX, REC8L1, SLC27A3, TGFB2, TLX2, TMEM22, TMEM30B, and UNC5C) were found to be methylated in at least 1 of 13 melanoma cell lines but not in two cultured normal melanocytes. Among these genes, Peroxiredoxin 2 (PRDX2) was expressed in normal melanocytes, and its expression was lost in melanomas with methylation. The loss of expression was restored by treatment of melanomas with a demethylating agent 5-aza-2'-deoxycytidine. In surgical melanoma specimens, methylation of PRDX2 was detected in 3 of 36 (8%). Furthermore, immunohistochemical analysis of PRDX2 showed that disappearance of immunoreactivity tends to associate with its methylation. PRDX2 was recently reported to be a negative regulator of platelet-derived growth factor signaling, and its silencing was suggested to be involved in melanomas. On the other hand, 12 CGIs were methylated in >or=9 of the 13 melanoma cell lines and are considered as candidate melanoma biomarkers.
Highlights
Methylation of promoter CpG islands (CGI) leads to transcriptional silencing of their downstream genes [1, 2]
Isolation of CGIs aberrantly methylated in melanoma cell lines
Methylation statuses of the putative core regions of the 54 CGIs were analyzed by methylation-specific PCR (MSP) of 13 melanoma cell lines and two cultured normal human epidermal melanocytes (HEM1 and HEM2)
Summary
Methylation of promoter CpG islands (CGI) leads to transcriptional silencing of their downstream genes [1, 2]. Tumor suppressor genes are inactivated by methylation of their promoter CGIs, along with mutations and loss of heterozygosity. Genes other than tumor suppressor genes are methylated in cancers [3]. If the methylation is specific to cancer cells, it can be used as a biomarker to detect cancer cells or cancer-derived DNA, taking advantage of the high sensitivity of methods to detect. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Nobeyama are recipients of Research Resident Fellowships from the Foundation for Promotion of Cancer Research
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