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DNMT1 and DNMT3b cooperate to silence genes in human cancer cells

Ina Rhee1, Kurtis E Bachman, Ben Ho Park

  • 1The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

Nature
|April 5, 2002
PubMed

Insights

Human cancer cells rely on two key enzymes, DNA methyltransferase 1 (DNMT1) and DNMT3B, for DNA methylation and gene silencing. Disrupting both significantly reduces methylation, impacting cancer cell growth.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Genetics

Background:

  • Tumor suppressor gene inactivation is crucial in cancer development, often via epigenetic silencing through hypermethylation.
  • Mechanisms of locus-specific and global DNA methylation in human cells are not fully understood.
  • While Dnmt1 is primary in mice, human cancer cells lacking DNMT1 retain substantial methylation.

Purpose of the Study:

  • To investigate the roles of DNMT1 and DNMT3B in maintaining DNA methylation and gene silencing in human cancer cells.
  • To determine the impact of combined DNMT1 and DNMT3B disruption on genomic methylation and cancer cell proliferation.

Main Methods:

  • Disruption of the human DNMT3B gene in a colorectal cancer cell line.
  • Genetic disruption of both DNMT1 and DNMT3B.
  • Assessment of global DNA methylation levels, repeated sequences, IGF2 imprinting, p16INK4a silencing, and cell growth.

Main Results:

  • Disrupting DNMT3B alone had minimal effect on global DNA methylation (<3%).
  • Simultaneous disruption of DNMT1 and DNMT3B nearly eliminated methyltransferase activity and reduced genomic methylation by >95%.
  • This led to demethylation of repeated sequences, loss of IGF2 imprinting, p16INK4a reactivation, and suppressed cancer cell growth.

Conclusions:

  • Two DNA methyltransferases, DNMT1 and DNMT3B, cooperatively maintain DNA methylation and gene silencing in human cancer cells.
  • DNA methylation is essential for the optimal proliferation of neoplastic cells.
  • Targeting these enzymes could offer therapeutic strategies for cancer treatment.

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