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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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DNMT3B gene amplification predicts resistance to DNA demethylating drugs

Laia Simó-Riudalbas1, Sónia A Melo, Manel Esteller

  • 1Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.

Genes, Chromosomes & Cancer
|April 13, 2011
PubMed

Insights

Cancer cells amplify the DNA methyltransferase 3B (DNMT3B) gene, leading to drug resistance. This finding supports DNMT3B as an oncogene and suggests copy number assays for demethylating agent trials.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Biology

Background:

  • Disruption of DNA methylation is common in human tumors.
  • Genetic alterations of DNA methyltransferases (DNMTs) are not well-described in carcinogenesis.

Purpose of the Study:

  • To investigate the role of DNA methyltransferases in cancer development.
  • To determine if gene amplification of DNMTs occurs in human cancers.
  • To assess the impact of DNMT gene dosage on drug sensitivity.

Main Methods:

  • Analysis of gene copy number, mRNA, and protein levels in pancreatic and breast cancer cells.
  • Assessing cell viability in response to DNA demethylating agents (5-azacytidine, Decitabine, SGI-1027).

Main Results:

  • Pancreatic and breast cancer cells exhibit gene amplification of DNA methyltransferase 3B (DNMT3B).
  • Increased DNMT3B gene dosage correlates with higher mRNA and protein levels.
  • Cancer cells with DNMT3B amplification show resistance to DNA demethylating agents, including 5-azacytidine and Decitabine.

Conclusions:

  • DNMT3B acts as a bona fide oncogene in human cancer.
  • Elevated DNMT3B gene dosage confers resistance to DNA demethylating drugs.
  • DNMT3B copy number assays are recommended for clinical trials involving demethylating agents in solid tumors.

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