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Increased expression of unmethylated CDKN2D by 5-aza-2'-deoxycytidine in human lung cancer cells

W G Zhu1, Z Dai, H Ding

  • 1Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University-Comprehensive Cancer Center, Columbus, OH 43210, USA.

Oncogene
|December 26, 2001
PubMed

Insights

Inhibition of DNA methylation can activate silenced genes and even unmethylated genes. Combined treatments showed synergistic effects on gene expression but also induced cytotoxicity, with p19(INK4d) exhibiting a distinct role.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • DNA hypermethylation in gene promoter regions typically silences transcription.
  • Hypomethylating agents can reactivate silenced genes, but their effect on unmethylated genes is less understood.
  • Histone acetylation is implicated in DNA methylation-mediated transcriptional silencing.

Purpose of the Study:

  • To investigate the impact of DNA methylation inhibition on both methylated and unmethylated genes.
  • To explore the combined effects of DNA methyltransferase and histone deacetylase inhibitors on gene expression and cell growth in lung cancer.
  • To elucidate the distinct roles of INK4 family members in response to epigenetic drug treatments.

Main Methods:

  • Analysis of CDKN2A and CDKN2D methylation status in human lung cancer cell lines.
  • Treatment with 5-aza-2'-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor.
  • Treatment with depsipeptide, a histone deacetylase inhibitor, alone and in combination with 5-Aza-CdR.
  • Quantification of p16(INK4a) and p19(INK4d) gene expression and assessment of cell growth.

Main Results:

  • 5-Aza-CdR treatment increased expression of both methylated CDKN2A (p16(INK4a)) and unmethylated CDKN2D (p19(INK4d)) in a dose- and duration-dependent manner.
  • Depsipeptide acted synergistically with 5-Aza-CdR to enhance p16(INK4a) and p19(INK4d) expression.
  • High concentrations of combined 5-Aza-CdR and depsipeptide decreased p16(INK4a) expression and suppressed cell growth, while further enhancing p19(INK4d) expression.

Conclusions:

  • Global DNA demethylation influences the expression of both methylated and unmethylated genes.
  • Combined inhibition of DNA methylation and histone deacetylation exhibits synergistic effects but can also lead to cytotoxicity.
  • p19(INK4d) plays a distinct role compared to other INK4 family members in response to epigenetic drug-induced cytotoxicity.

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