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Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors

Michael Daskalakis1,2, David Brocks1, Yi-Hua Sheng3

  • 1a Division of Epigenomics and Cancer Risk Factors , German Cancer Research Center , Heidelberg , Germany.

Cell Cycle (Georgetown, Tex.)
|April 11, 2018
PubMed

Insights

Epigenetic drugs like DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis) activate endogenous retroviruses. This triggers antiviral responses and apoptosis, offering new insights into cancer treatment mechanisms.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Epigenetic drugs, including DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis), are crucial in treating certain cancers.
  • Their precise mechanisms of action, particularly regarding human endogenous retroviral elements (HERVs), remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular effects of DNMTis and HDACis.
  • To highlight the role of these epigenetic drugs in activating long terminal repeats (LTRs) derived from HERVs.
  • To present novel in vitro and in vivo data on epigenetic drug treatment.

Main Methods:

  • Review of current knowledge on epigenetic drug mechanisms.
  • Analysis of LTR activation induced by DNMTis and HDACis.
  • Presentation of new experimental data from in vitro and in vivo studies.

Main Results:

  • Epigenetic drugs induce activation of HERVs, leading to double-stranded RNA (dsRNA) synthesis.
  • Activation of LTR promoters results in non-annotated transcripts, potentially encoding novel proteins.
  • dsRNA synthesis triggers an antiviral response pathway, culminating in apoptosis.

Conclusions:

  • Epigenetic drugs exert molecular effects through HERV activation and LTR promoter stimulation.
  • These mechanisms contribute to the therapeutic efficacy of DNMTis and HDACis in malignancies.
  • Novel insights into epigenetic drug action provide a foundation for future cancer therapies.
Keywords:
Epigenetic therapyendogenous retroviral elementsviral mimicry

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