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Summary: Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation. [ABSTRACT FROM AUTHOR]

Summary: Cancer cells simultaneously harbor global losses and gains in DNA methylation. We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin. DNMT1 becomes part of a complex(es) containing DNMT3B and members of the polycomb repressive complex 4. Hydrogen peroxide treatment causes relocalization of these proteins from non-GC-rich to GC-rich areas. Key components are similarly enriched at gene promoters in an in vivo colitis model. Although high-expression genes enriched for members of the complex have histone mark and nascent transcription changes, CpG island-containing low-expression genes gain promoter DNA methylation. Thus, oxidative damage induces formation and relocalization of a silencing complex that may explain cancer-specific aberrant DNA methylation and transcriptional silencing. [ABSTRACT FROM AUTHOR]