Demethylation links cell fate and cancer

Access through your institution Buy or subscribe 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. Dysregulation 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. This is

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during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES ORIGINAL RESEARCH PAPER * Rai, K. et al.

DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC. _Cell_ 142, 930–942 (2010) Article  CAS  Google Scholar  FURTHER READING * Law, J. A.

& Jacobsen S. E. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. _Nature Rev. Genet._ 11, 204–220 (2010) Article  CAS  Google Scholar  Download

references Authors * Meera Swami View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE

THIS ARTICLE Swami, M. Demethylation links cell fate and cancer. _Nat Rev Genet_ 11, 749 (2010). https://doi.org/10.1038/nrg2890 Download citation * Published: 05 October 2010 * Issue Date:

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