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DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors

Richard J Honeywell1, Dzjemma Sarkisjan1, Michael H Kristensen2

  • 1a Department of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands.

Nucleosides, Nucleotides & Nucleic Acids
|January 22, 2019
PubMed

Insights

DNA methyltransferase 1 (DNMT1) shows significant variation in expression across various cancers. This variability suggests DNMT1 could be a predictive biomarker for demethylating therapies like RX-3117.

Area of Science:

  • Oncology
  • Epigenetics
  • Pharmacology

Background:

  • Aberrant DNA methylation is a hallmark of cancer.
  • DNA methyltransferases (DNMTs) regulate DNA methylation and are targets for cancer therapy.
  • RX-3117 is a novel demethylating agent in clinical trials for bladder and pancreatic cancers.

Purpose of the Study:

  • To investigate DNA methyltransferase 1 (DNMT1) expression as a potential predictive biomarker for demethylating therapy.
  • To assess DNMT1 protein and mRNA expression in various cancer models and patient samples.

Main Methods:

  • Analysis of DNMT1 mRNA and protein expression in 19 cancer cell lines.
  • Evaluation of DNMT1 expression in 26 human xenografts representing diverse cancer types.
  • Comparison of DNMT1 expression and DNA methylation levels in colorectal cancer patient tumors versus adjacent normal tissue.

Main Results:

  • Significant variation in DNMT1 mRNA expression was observed across cell lines (100-fold) and xenografts (1100-fold).
  • DNMT1 protein was overexpressed in colorectal tumors compared to non-malignant mucosa (P=0.02).
  • Tumor tissues showed significantly higher DNA methylation than normal tissues (P=0.001).

Conclusions:

  • The substantial variation in DNMT1 expression suggests its potential as a predictive biomarker.
  • DNMT1 may guide the selection of patients who could benefit from demethylating agents like RX-3117.
Keywords:
DNA methylationDNA methyltransferaseRX-3117

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