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DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs

Hongshan Guo1, Joanna A Vuille2, Ben S Wittner2

  • 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Cell
|June 16, 2023
PubMed

Insights

Early prostate cancer involves DNA hypomethylation, silencing immune genes like CD1 and IFI16. Reactivating these genes in mice stopped tumor growth, highlighting epigenetics in cancer immunity.

Area of Science:

  • Genomic epigenetics
  • Cancer biology
  • Immunology

Background:

  • Cancer exhibits DNA hypomethylation, leading to gene silencing in large chromatin domains, but its role in tumorigenesis is unclear.
  • Prostate malignancy progression involves epigenetic alterations, including DNA methylation changes.

Purpose of the Study:

  • To identify and characterize early DNA hypomethylation domains in prostate cancer.
  • To investigate the role of these hypomethylation domains in gene silencing and tumorigenesis.
  • To explore the potential of targeting these epigenetic changes for cancer therapy.

Main Methods:

  • High-resolution, genome-wide, single-cell DNA methylation sequencing.
  • Analysis of DNA methylation patterns from early prostate malignancy to metastatic circulating tumor cells (CTCs).
  • Gene expression analysis and functional studies in immuno-competent mouse models.

Main Results:

  • Identified 40 core hypomethylation domains uniformly present from early prostate cancer to metastatic CTCs.
  • Discovered that silenced genes within these domains are enriched for immune-related genes, including CD1 and interferon-inducible genes (IFI16).
  • Demonstrated that re-expressing CD1 or IFI16 orthologs in mice abrogated tumorigenesis and activated anti-tumor immunity.

Conclusions:

  • Early epigenetic changes, specifically DNA hypomethylation domains, significantly shape tumorigenesis by silencing key immune genes.
  • These findings suggest that targeting specific epigenetic alterations could be a viable strategy for cancer immunotherapy.
  • Hypomethylation domains are detectable in blood, offering potential for non-invasive cancer detection via CTCs.
Keywords:
CD1ADNA hypomethylationIFI16NKT cellscirculating tumor cellsimmune surveillancelipid antigensprostate cancersingle-cell sequencingtumorigenesis

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