Mismatch repair proteins initiate epigenetic alterations during inflammation-driven tumorigenesis

Ashley R. Maiuri, Michael Peng, Shruthi Sriramkumar, Caitlin M. Kamplain, Christina E. DeStefano Shields, Cynthia L. Sears, Heather M. O'Hagan

Research output: Contribution to journalArticlepeer-review


Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared with normal epithelium and noninflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hyper-methylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis.

Original languageEnglish (US)
Pages (from-to)3467-3478
Number of pages12
JournalCancer Research
Issue number13
StatePublished - Jul 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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