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An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues
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Epigenetic approaches to cancer therapy

J A Plumb1, N Steele, P W Finn

  • 1CRUK Centre for Oncology and Applied Pharmacology, Beatson Laboratories, University of Glasgow, Garscube Estate, Glasgow G61 1BD, UK. Jane.Plumb@beatson.gla.ac.uk

Biochemical Society Transactions
|October 28, 2004
PubMed

Insights

DNA methylation and histone deacetylation impact gene expression and drug resistance. Combining DNA methyltransferase inhibitor DAC with histone deacetylase inhibitor PXD101 re-expresses MLH1, enhancing cisplatin chemotherapy efficacy in resistant tumors.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Pharmacology

Background:

  • Histone deacetylation and DNA methylation regulate gene expression, including tumor suppressor genes.
  • Methylation of the hMLH1 gene promoter causes DNA mismatch repair loss, leading to cisplatin resistance.

Purpose of the Study:

  • To investigate the potential of combining epigenetic drugs to overcome cisplatin resistance.
  • To evaluate the efficacy of a DNA methyltransferase inhibitor (DAC) and a histone deacetylase inhibitor (PXD101) in restoring MLH1 expression and chemosensitivity.

Main Methods:

  • Utilized cisplatin-resistant A2780/cp70 cell lines and tumor-bearing mice models.
  • Administered 2-deoxy-5'-azacytidine (DAC) to inhibit DNA methylation and PXD101 to inhibit histone deacetylase.
  • Assessed MLH1 re-expression, DNA methylation status, and sensitivity to cisplatin.

Main Results:

  • DAC treatment partially reversed DNA methylation and restored MLH1 expression, sensitizing cells to cisplatin.
  • Combined treatment with DAC and PXD101 in tumor-bearing mice significantly increased MLH1 re-expression.
  • The combination therapy showed enhanced anti-tumor effects compared to monotherapy.

Conclusions:

  • Combined epigenetic therapy with DAC and PXD101 can re-sensitize cisplatin-resistant tumors by restoring MLH1 expression.
  • This combination strategy holds promise for improving chemotherapy efficacy in patients with hMLH1 promoter methylation-driven resistance.
  • Further investigation is warranted to explore the clinical application of this combined epigenetic approach.

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