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Global identification of genes targeted by DNMT3b for epigenetic silencing in lung cancer

I Teneng1, C S Tellez1, M A Picchi1

  • 1Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.

Oncogene
|January 29, 2014
PubMed

Insights

DNA methyltransferase DNMT3b drives early cancer development by silencing tumor suppressor genes. Restoring MAL and OLIG2 expression inhibited lung tumor growth, highlighting DNMT3b as a therapeutic target in non-small-cell lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • DNA methylation is crucial for gene regulation and implicated in cancer.
  • DNMT1 and DNMT3b are key enzymes in DNA methylation.
  • Aberrant DNA methylation contributes to cancer development.

Purpose of the Study:

  • To investigate the role of DNMT3b in early stages of lung cancer development.
  • To identify DNMT3b-targeted genes silenced during transformation.
  • To explore the therapeutic potential of re-expressing silenced tumor suppressor genes.

Main Methods:

  • Used hTERT/CDK4-immortalized human bronchial epithelial cells (HBECs) treated with tobacco carcinogens.
  • Performed genome-wide profiling to identify DNMT3b target genes.
  • Utilized in vivo xenograft models to assess tumor suppressor gene function.

Main Results:

  • DNMT3b expression increased significantly in pre-cancerous cells, accelerating carcinogen-induced transformation.
  • Identified 143 DNMT3b target genes, many regulated by PRC2 and silenced via methylation in non-small-cell lung cancer (NSCLC).
  • Re-expression of tumor suppressors MAL and OLIG2 inhibited lung tumor xenograft growth.

Conclusions:

  • DNMT3b plays a critical role in the initiation of lung cancer by establishing aberrant DNA methylation.
  • Provides a comprehensive catalog of DNMT3b-silenced genes in NSCLC.
  • MAL and OLIG2 function as tumor suppressors, and their re-expression offers a potential therapeutic strategy for NSCLC.

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