Related Experiment Video

Updated: Apr 4, 2026

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

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Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Katherine B Chiappinelli1, Pamela L Strissel2, Alexis Desrichard3

  • 1Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.

Cell
|August 29, 2015
PubMed

Insights

DNA methyltransferase inhibitors (DNMTis) activate cancer immune signaling via viral defense pathways. This triggers apoptosis in ovarian cancer and sensitizes melanoma to immunotherapy, highlighting a new therapeutic strategy.

Area of Science:

  • Immunology
  • Oncology
  • Epigenetics

Background:

  • DNA methyltransferase inhibitors (DNMTis) are investigated for cancer therapy.
  • Immune signaling pathways are crucial in anti-tumor responses.
  • Endogenous retroviruses (ERVs) and viral defense mechanisms are implicated in cancer.

Purpose of the Study:

  • To elucidate the mechanism by which DNMTis modulate immune signaling in cancer.
  • To investigate the role of viral defense pathways and ERVs in DNMTi-induced anti-cancer effects.
  • To assess the potential of viral defense gene expression as a biomarker for immunotherapy response.

Main Methods:

  • Treatment of ovarian cancer cells with DNMTis.
  • Analysis of cytosolic sensing of double-stranded RNA (dsRNA) and type I interferon response.
  • Knockdown of dsRNA sensors (TLR3, MAVS) and blockade of interferon beta or its receptor.
  • Gene expression analysis of endogenous retroviruses (ERVs) and viral defense genes.
  • Correlation analysis of gene expression in primary ovarian cancer and The Cancer Genome Atlas (TCGA) datasets.
  • Analysis of viral defense signature in melanoma patient tumors treated with immune checkpoint therapy.
  • Pre-clinical melanoma model studies with DNMTi and anti-CTLA4 therapy.

Main Results:

  • DNMTis upregulate immune signaling through the viral defense pathway in cancer.
  • In ovarian cancer, DNMTis induce dsRNA sensing, type I interferon response, and apoptosis.
  • Knockdown of TLR3/MAVS or blocking interferon signaling significantly reduces DNMTi effects.
  • Overexpression of hypermethylated ERV genes accompanies the immune response, and ERV overexpression activates it.
  • Basal ERV and viral defense gene expression correlate in ovarian cancer and stratify TCGA samples.
  • High viral defense signature in melanoma tumors predicts durable response to immune checkpoint therapy.
  • DNMTi treatment sensitizes melanoma to anti-CTLA4 therapy in a pre-clinical model.

Conclusions:

  • DNMTis harness the innate viral defense pathway to enhance anti-cancer immunity.
  • The ERV-viral defense axis is a key mediator of DNMTi efficacy.
  • Viral defense gene expression signatures may predict response to immunotherapy and guide treatment strategies.

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