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Epigenetics

Demethylation links cell fate and cancer

Nature Reviews Cancer volume 10, pages 740–741 (2010)Cite this article

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Previous studies have shown that adenoma formation after loss of the tumour suppressor gene adenomatous polyposis coli (APC) is reduced by inhibition of DNMT1. These findings suggest that APC may normally function to regulate levels of DNA methylation. To investigate how such regulation occurs, Rai and colleagues examined zebrafish embryos with homozygous apc mutations. Components of the DNA demethylase system were upregulated in this setting, accompanied by promoter hypomethylation of many genes involved in intestinal fate and colorectal cancer development. Knockdown of demethylase components restored normal levels of methylation. Together, these results suggest that the demethylase system is responsible for hypomethylation of target genes in involved in fate decisions, but that hypomethylation is prevented when APC is active. The authors also showed that this scenario is relevant to human cancer — APC-mutant colon adenomas showed upregulation of demethylase components and concomitant hypomethylation of a set of promoters that overlapped with those identified in zebrafish.

APC controls both Wnt signalling and retinoic acid (RA) biosynthesis; is one of these mechanisms responsible for the upregulation of demethylase components after APC loss? The authors treated apc-mutant embryos with RA or an inhibitor of β-catenin, a component of Wnt signalling. Deregulation of Wnt signalling did not affect expression of demethylase components; however, RA treatment reversed the upregulation of the demethylase components induced by apc mutation, suggesting that RA is involved in regulation of DNA demethylase.

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References

ORIGINAL RESEARCH PAPER

  1. Rai, K. et al. DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC. Cell 142, 930–942 (2010)

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FURTHER READING

  1. Law, J. A. & Jacobsen S. E. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nature Rev. Genet. 11, 204–220 (2010)

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Authors
  1. Meera Swami
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Swami, M. Demethylation links cell fate and cancer. Nat Rev Cancer 10, 740–741 (2010). https://doi.org/10.1038/nrc2948

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