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Intragenic long interspersed element-1 sequences promote promoter hypermethylation in lung adenocarcinoma, multiple myeloma and prostate cancer

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Abstract

In cancers, although the methylation of long interspersed element- 1 sequences (LINE-1s) and tumor suppressor gene promoters are modified in the opposite direction, LINE-1 hypomethylation and promoter hypermethylation of some loci are directly associated. During carcinogenesis, the reduction in LINE-1 methylation occurs. Intragenic LINE-1s produces antisense RNA in introns and reduces mRNA transcription levels. Several antisense RNAs have been reported to mediate methylation of the associated CpG islands. Here we compared genome-wide promoter methylation and expression profiles of LINE-1-hypomethylated malignancies, reported in the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo), including lung adenocarcinoma, multiple myeloma and prostate cancer. Then we analysed a microarray experiment if promoters of a set of genes containing LINE-1s or Alu are commonly methylated. Finally, the differences in structural characteristics of LINE-1s were compared between LINE-1 groups. Here we found that genes that contained LINE-1s were frequently repressed (p < 0.01) and possessed promoter hypermethylation (p < 1.0E-4). The expression levels of genes containing LINE-1s with promoter hypermethylation were the lowest. Finally, the genomic distributions of gene-repressing LINE-1s and promoter-hypermethylating LINE-1s were neither co-segregated nor randomly segregated. In conclusion, cancer-associated intragenic LINE-1 epigenetic change promotes promoter hypermethylation and represses gene expression. These two mechanisms are independently influenced by genomic locations but synergistically down-regulate genes.

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Authors and Affiliations

  1. Inter-Department Program of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand

    Suphakit Khowutthitham & Chumpol Ngamphiw

  2. Genome Institute, National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Paholyothin Road, Klong 1, Klong Luang, Pathum Thani, 12120, Thailand

    Chumpol Ngamphiw & Sissades Tongsima

  3. Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand

    Wachiraporn Wanichnopparat & Kulachanya Suwanwongse

  4. Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Rama IV, Bangkok, 10330, Thailand

    Chatchawit Aporntewan

  5. Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand

    Apiwat Mutirangura

  6. Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, 10330, Thailand

    Sissades Tongsima, Chatchawit Aporntewan & Apiwat Mutirangura

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  1. Suphakit Khowutthitham
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  2. Chumpol Ngamphiw
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  4. Kulachanya Suwanwongse
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  6. Chatchawit Aporntewan
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  7. Apiwat Mutirangura
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Correspondence to Apiwat Mutirangura.

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SK, CN and WW contributed equally to this work.

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Khowutthitham, S., Ngamphiw, C., Wanichnopparat, W. et al. Intragenic long interspersed element-1 sequences promote promoter hypermethylation in lung adenocarcinoma, multiple myeloma and prostate cancer. Genes Genom 34, 517–528 (2012). https://doi.org/10.1007/s13258-012-0058-0

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