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

Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contri-bution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identify 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic circulating tumor cells (CTCs). Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are en-riched for immune-related genes; prominent among these is a single gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes implicated in innate immunity. The re-expression of CD1 or IFI16 murine orthologs in immuno-competent mice abro-gates tumorigenesis, accompanied by the activation of anti-tumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs.

Automated summary

Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, but its contribution to tumorigenesis is uncertain. Through single-cell DNA methylation sequencing, researchers identify core domains that are hypomethylated in prostate malignancy from early stages to metastatic circulating tumor cells (CTCs). Some smaller loci within these domains have preserved methylation and contain cell proliferation genes. Transcriptionally silenced genes within the hypomethylated domains are enriched for immune-related genes, including a gene cluster harboring CD1 genes and IFI16-related genes linked to innate immunity. Restoring CD1 or IFI16 expression in mice with intact immune systems inhibits tumorigenesis and activates anti-tumor immunity. Hypomethylation domains can be detected in blood samples enriched for CTCs.