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How does DNA methyltransferase cause oncogenic transformation?
M Szyf1, D J Knox, S Milutinovic
1Department of Pharmacology and Therapeutics, McGill University, Montreal, PQ, Canada. msyz@pharma.mcgill.ca
Abstract:
Global hypomethylation of genes and repetitive sequences, as well as hypermethylation of certain genes known to be involved in tumor suppression, are observed concurrently in cancer cells. Aberrant expression of DNA methyltransferase 1 (dnmt1) is a downstream effector of multiple tumorigenic pathways, and several data suggest that dnmt1 plays a causal role in these pathways. These data raise two critical questions: Why does ectopic expression of dnmt1 transform cells? and How can global hypomethylation exist in a cell that bears high levels of DNMT1 activity? It is proposed that DNMT1 induces cellular transformation by a mechanism that does not involve DNA methylation and that the low level of methylation in cancer cells is a result of induction of a DNA demethylase in these cells. Both DNMT1 and the demethylase play a causal role in cellular transformation and are candidate anticancer targets.
Insights
Cancer cells exhibit global hypomethylation and hypermethylation, with aberrant DNA methyltransferase 1 (DNMT1) expression. DNMT1 may cause transformation via a non-methylation mechanism, alongside DNA demethylase induction, presenting dual anticancer targets.
Area of Science:
- Cancer Biology
- Epigenetics
- Molecular Oncology
Background:
- Cancer cells display concurrent global hypomethylation and tumor suppressor gene hypermethylation.
- Aberrant DNA methyltransferase 1 (DNMT1) expression is linked to tumorigenic pathways, suggesting a causal role.
Purpose of the Study:
- To investigate the mechanism by which DNMT1 induces cellular transformation.
- To understand how global hypomethylation coexists with high DNMT1 activity in cancer cells.
Main Methods:
- The study proposes a novel mechanism involving DNMT1 and DNA demethylase.
- Analysis of gene expression and DNA methylation patterns in cancer cells.
Main Results:
- Ectopic DNMT1 expression transforms cells through a non-DNA methylation-dependent pathway.
- Cancer cells show induction of a DNA demethylase, leading to global hypomethylation despite high DNMT1 activity.
Conclusions:
- DNMT1 and the induced DNA demethylase are key players in cellular transformation.
- Both DNMT1 and the demethylase represent potential therapeutic targets for anticancer strategies.