DNA methyltransferase inhibition reduces inflammation-induced colon tumorigenesis

Ashley R. Maiuri, Sudha S. Savant, Ram Podicheti, Douglas B. Rusch, Heather M. O’Hagan

Research output: Contribution to journalArticle

Abstract

Chronic inflammation is strongly associated with an increased risk of developing colorectal cancer. DNA hypermethylation of CpG islands alters the expression of genes in cancer cells and plays an important role in carcinogenesis. Chronic inflammation is also associated with DNA methylation alterations and in a mouse model of inflammation-induced colon tumorigenesis, we previously demonstrated that inflammation-induced tumours have 203 unique regions with DNA hypermethylation compared to uninflamed epithelium. To determine if altering inflammation-induced DNA hypermethylation reduces tumorigenesis, we used the same mouse model and treated mice with the DNA methyltransferase (DNMT) inhibitor decitabine (DAC) throughout the tumorigenesis time frame. DAC treatment caused a significant reduction in colon tumorigenesis. The tumours that did form after DAC treatment had reduced inflammation-specific DNA hypermethylation and alteration of expression of associated candidate genes. When compared, inflammation-induced tumours from control (PBS-treated) mice were enriched for cell proliferation associated gene expression pathways whereas inflammation-induced tumours from DAC-treated mice were enriched for interferon gene signatures. To further understand the altered tumorigenesis, we derived tumoroids from the different tumour types. Interestingly, tumoroids derived from inflammation-induced tumours from control mice maintained many of the inflammation-induced DNA hypermethylation alterations and had higher levels of DNA hypermethylation at these regions than tumoroids from DAC-treated mice. Importantly, tumoroids derived from inflammation-induced tumours from the DAC-treated mice proliferated more slowly than those derived from the inflammation-induced tumours from control mice. These studies suggest that inhibition of inflammation-induced DNA hypermethylation may be an effective strategy to reduce inflammation-induced tumorigenesis.

Original languageEnglish (US)
Pages (from-to)1209-1223
Number of pages15
JournalEpigenetics
Volume14
Issue number12
DOIs
StatePublished - Dec 2 2019

Fingerprint

Methyltransferases
Colon
Carcinogenesis
Inflammation
DNA
Neoplasms
decitabine
Gene Expression
CpG Islands
Neoplasm Genes
DNA Methylation
Interferons
Genes
Colorectal Neoplasms
Epithelium

Keywords

  • colon cancer
  • decitabine
  • DNA methylation
  • Inflammation
  • interferon signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

DNA methyltransferase inhibition reduces inflammation-induced colon tumorigenesis. / Maiuri, Ashley R.; Savant, Sudha S.; Podicheti, Ram; Rusch, Douglas B.; O’Hagan, Heather M.

In: Epigenetics, Vol. 14, No. 12, 02.12.2019, p. 1209-1223.

Research output: Contribution to journalArticle

Maiuri, Ashley R. ; Savant, Sudha S. ; Podicheti, Ram ; Rusch, Douglas B. ; O’Hagan, Heather M. / DNA methyltransferase inhibition reduces inflammation-induced colon tumorigenesis. In: Epigenetics. 2019 ; Vol. 14, No. 12. pp. 1209-1223.
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