Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis

Cancer Research
Ashley R MaiuriHeather M O'Hagan

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. Hypermethylated 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 ...Continue Reading

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Citations

Dec 15, 2018·Environmental and Molecular Mutagenesis·Ning DingHeather M O'Hagan
Mar 20, 2019·Infection and Immunity·Jawara AllenWinston Timp
Dec 14, 2018·Genes·Marthe LaisnéPierre-Antoine Defossez
Oct 19, 2019·British Journal of Pharmacology·Megan BeetchBarbara Stefanska
Jun 27, 2019·Epigenetics : Official Journal of the DNA Methylation Society·Ashley R MaiuriHeather M O'Hagan
Dec 21, 2019·Expert Review of Molecular Diagnostics·Tengqi WangLizhou Jia
Dec 16, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Yinghui ZhaoAjay Goel
Jul 10, 2021·The Journal of Nutritional Biochemistry·Megan BeetchBarbara Stefanska
Aug 21, 2021·Journal of the National Comprehensive Cancer Network : JNCCN·Reece J Knippel, Cynthia L Sears
Aug 28, 2021·Antioxidants·Sadaf Harandi-ZadehBarbara Stefanska
Aug 18, 2021·Cancer Discovery·Reece J KnippelCynthia L Sears

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