The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury

// Amy Marie Yu 1 , Jennifer A. Calvo 1, 2 , Suresh Muthupalani 3 , Leona D. Samson 1, 2, 4, 5 1 Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA 2 Biology Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA 3 Department of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA 4 Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA 5 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA Correspondence to: Leona D. Samson, email: lsamson@mit.edu Keywords: Mbd4, colon cancer, inflammation, ulcerative colitis, AOM/DSS Received: February 17, 2016 Accepted: March 28, 2016 Published: April 13, 2016 ABSTRACT Much of the global cancer burden is associated with longstanding inflammation accompanied by release of DNA-damaging reactive oxygen and nitrogen species. Here, we report that the Mbd4 DNA glycosylase is protective in the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model of inflammation-driven colon cancer. Mbd4 excises T and U from T:G and U:G mismatches caused by deamination of 5-methylcytosine and cytosine. Since the rate of deamination is higher in inflamed tissues, we investigated the role of Mbd4 in inflammation-driven tumorigenesis. In the AOM/DSS assay, Mbd4 –/– mice displayed more severe clinical symptoms, decreased survival, and a greater tumor burden than wild-type (WT) controls. The increased tumor burden in Mbd4 –/– mice did not arise from impairment of AOM-induced apoptosis in the intestinal crypt. Histopathological analysis indicated that the colonic epithelium of Mbd4 –/– mice is more vulnerable than WT to DSS-induced tissue damage. We investigated the role of the Mbd4 –/– immune system in AOM/DSS-mediated carcinogenesis by repeating the assay on WT and Mbd4 –/– mice transplanted with WT bone marrow. Mbd4 –/– mice with WT bone marrow behaved similarly to Mbd4 –/– mice. Together, our results indicate that the colonic epithelium of Mbd4 –/– mice is more vulnerable to DSS-induced injury, which exacerbates inflammation-driven tissue injury and cancer.