The role of Line-1 methylation on gene promoter methylation in head and neck cancer

Abstract

In cancers, hypermethylation of CpG dinucleotides in promoter region and global hypomethylation are commonly featured. Global hypomethylation can lead to alterations in the expression of oncogenes, chromosomal instability and reactivation of transposons. LINE-1 elements are the most autonomous non LTR retrotransposon in human genome by mass and suppressed by DNA methylation process. The methylation levels of LINE-1 elements in cancerous cells were lower than wild-type cells in various tissues and different among tissue types and inserted locations. However, some intragenic LINE-1 elements hypermethylation can be found sporadically in cancer such as intragenic LINE-1 element that located on CNTNAP5. Here, we studied the influence of LINE-1 methylation, both intragenic LINE-1 and global LINE-1 elements, on gene promoter methylation in head and neck cancer cell lines. We selected candidate hypermethylated genes with and without LINE-1 insertion, and then investigated the methylation levels of their promoters, intragenic LINE-1 and global LINE-1 elements. The result showed that LINE-1 methylation in cancerous cells was also lower than normal cells. In addition, intragenic LINE-1 methylation in the same gene especially located on the same intron might have the highest correlation value. Then, we observed the correlation between gene promoter methylation and LINE-1 methylation; both intragenic and global LINE-1 methylation. We found that global LINE-1 hypomethylation was correlated to both promoter of LINE-1 inserted gene (CNTNAP5) and non-LINE-1 inserted gene (CALCA) which were demethylated promoters. These data indicated that the correlation between global hypomethylation and gene promoter methylation were associated in an intragenic LINE-1-independent manner, and that mechanism of global hypomethylation was general process which sequences-dependent manner.