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 journalArticle

12 Scopus citations

Abstract

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
Volume77
Issue number13
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Maiuri, A. R., Peng, M., Sriramkumar, S., Kamplain, C. M., DeStefano Shields, C. E., Sears, C. L., & O'Hagan, H. M. (2017). Mismatch repair proteins initiate epigenetic alterations during inflammation-driven tumorigenesis. Cancer Research, 77(13), 3467-3478. https://doi.org/10.1158/0008-5472.CAN-17-0056