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

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.