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Inhibitors of DNA Methylation, Histone Deacetylation, and Histone Demethylation: A Perfect Combination for Cancer

C A Zahnow1, M Topper1, M Stone1

  • 1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States.

Advances in Cancer Research
|April 3, 2016
PubMed

Insights

Cancer involves gene expression changes due to epigenetic alterations. Combining DNA-demethylating agents with histone modifiers offers a promising epigenetic therapy strategy for solid tumors.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Biology

Background:

  • Epigenetic alterations, including DNA hypermethylation and histone modifications, are hallmarks of cancer, driving aberrant gene expression.
  • These epigenetic changes involve DNA methylation, histone deacetylation/methylation, and transcriptional corepressor recruitment, leading to gene silencing or altered chromatin structure.
  • The reversible nature of these epigenetic marks presents opportunities for therapeutic intervention.

Purpose of the Study:

  • To review the potential benefits of combining DNA-demethylating agents with histone deacetylase (HDAC) inhibitors or lysine-specific demethylase (LSD) inhibitors in epigenetic cancer therapy.
  • To explore the synergistic or additive effects of these combined epigenetic therapies in solid tumors.
  • To highlight the mechanisms of action underlying the antitumor responses to combined epigenetic treatments.

Main Methods:

  • Literature review focusing on preclinical and clinical studies of combined epigenetic therapies.
  • Analysis of studies investigating the interplay between DNA methylation, histone acetylation, and histone methylation in cancer.
  • Examination of research on DNA-demethylating agents, HDAC inhibitors, and LSD inhibitors.

Main Results:

  • Combined epigenetic therapies demonstrate potential for enhanced antitumor activity compared to single-agent treatments.
  • Synergistic effects are observed through the coordinated reversal of aberrant epigenetic silencing and restoration of gene expression.
  • Mechanisms include re-sensitization of cancer cells to apoptosis and inhibition of tumor growth and metastasis.

Conclusions:

  • Combination epigenetic therapy, particularly involving DNA-demethylating agents and histone-modifying enzymes inhibitors, holds significant promise for solid tumor treatment.
  • Understanding the intricate mechanisms of action is crucial for optimizing therapeutic strategies and improving patient outcomes.
  • Further clinical investigation is warranted to fully realize the therapeutic potential of these combined epigenetic approaches.
Keywords:
DNA methyltransferase inhibitorsDrug synergyEpigenetic therapyHistone deacetylation and methylation inhibitorsSolid tumors

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