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TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells

Masahiro Kai1, Takeshi Niinuma1, Hiroshi Kitajima1

  • 1Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Plos One
|December 16, 2016
PubMed

Insights

Loss of TET1 enzyme in colorectal cancer (CRC) cells leads to widespread DNA methylation changes. This TET1 depletion also reduces the effectiveness of epigenetic drugs, impacting CRC treatment strategies.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Aberrant DNA methylation is a hallmark of colorectal cancer (CRC), but its mechanisms remain unclear.
  • Reduced 5-hydroxymethylcytosine and TET1 expression are observed in CRC.
  • Epigenetic silencing of TET1 is linked to the CpG island methylator phenotype in CRC.

Purpose of the Study:

  • To investigate the relationship between TET1 loss and aberrant DNA methylation in colorectal cancer.
  • To determine the functional consequences of TET1 depletion on DNA methylation patterns and gene expression in CRC cells.

Main Methods:

  • Stable TET1 knockdown was established in Colo320DM (high TET1) and HCT116 (normal TET1 levels) CRC cell lines.
  • Infinium HumanMethylation450 BeadChip assays were employed to analyze genome-wide DNA methylation.
  • Gene expression profiles were assessed following TET1 depletion and treatment with 5-aza-2'-deoxycytidine.

Main Results:

  • TET1 depletion in Colo320DM cells caused significant increases in 5-methylcytosine at over 10,000 CpG sites, affecting promoters, gene bodies, and intergenic regions.
  • Altered DNA methylation in TET1-depleted cells impacted the expression of a subset of genes.
  • TET1 knockdown did not significantly alter DNA methylation in HCT116 cells but attenuated the gene expression effects of 5-aza-2'-deoxycytidine in both cell lines.

Conclusions:

  • Loss of TET1 function may contribute to aberrant DNA methylation patterns observed in colorectal cancer.
  • TET1 depletion can reduce the efficacy of DNA methyltransferase inhibitors like 5-aza-2'-deoxycytidine in CRC cells.
  • These findings highlight TET1's role in maintaining DNA methylation homeostasis and its potential as a therapeutic target in CRC.

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