Abstract
Aberrant DNA methylation is commonly observed in colorectal cancer (CRC), but the underlying mechanism is not fully understood. 5-hydroxymethylcytosine levels and TET1 expression are both reduced in CRC, while epigenetic silencing of TET1 is reportedly associated with the CpG island methylator phenotype. In the present study, we aimed to clarify the relationship between loss of TET1 and aberrant DNA methylation in CRC. Stable TET1 knockdown clones were established using Colo320DM cells, which express high levels of TET1, and HCT116 cells, which express TET1 at a level similar to that in normal colonic tissue. Infinium HumanMethylation450 BeadChip assays revealed increased levels of 5-methylcytosine at more than 10,000 CpG sites in TET1-depleted Colo320DM cells. Changes in DNA methylation were observed at various positions within the genome, including promoters, gene bodies and intergenic regions, and the altered methylation affected expression of a subset of genes. By contrast, TET1 knockdown did not significantly affect DNA methylation in HCT116 cells. However, TET1 depletion was associated with attenuated effects of 5-aza-2’-deoxycytidine on gene expression profiles in both cell lines. These results suggest that loss of TET1 may induce aberrant DNA methylation and may attenuate the effect of 5-aza-2’-deoxycytidine in CRC cells.
Highlights
Cancers are thought to develop through accumulation of genetic and epigenetic alterations
We found that colorectal cancer (CRC) in the CpG island methylator phenotype (CIMP)-high category showed significantly lower levels of TET1 expression than CIMP-low or CIMP-negative tumors (Fig 1A), which is consistent with previous observations
To explore the effect of TET1 downregulation in CRC cells, we selected for knockdown experiments HCT116 cells, in which TET1 is expressed at a level similar to that in normal colon, and Colo320DM cells, in which TET1 is expressed at a higher level than in normal colon
Summary
Cancers are thought to develop through accumulation of genetic and epigenetic alterations. A well-documented epigenetic alteration in human malignancies is aberrant DNA methylation. DNA methylation is catalyzed by DNA methyltransferases (DNMTs), mainly at the C-5 position of cytosine (5-mC) in CpG dinucleotides. Cancer cells typically exhibit two patterns of abnormal DNA methylation: regional hypermethylation and global hypomethylation. Hypermethylation at gene promoter regions, especially CpG islands, is one of the major mechanisms by which tumor-related genes are inactivated in cancer. A subset of PLOS ONE | DOI:10.1371/journal.pone.0168281. A subset of PLOS ONE | DOI:10.1371/journal.pone.0168281 December 15, 2016
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