Folic Acid Supplementation Promotes Hypomethylation in Both the Inflamed Colonic Mucosa and Colitis-Associated Dysplasia

Wen Chi L. Chang, Jayashri Ghosh, Harry S. Cooper, Lisa Vanderveer, Bryant Schultz, Yan Zhou, Kristen N. Harvey, Esther Kaunga, Karthik Devarajan, Yuesheng Li, Jaroslav Jelinek, Mariana F. Fragoso, Carmen Sapienza, Margie L. Clapper

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


PURPOSE: The purpose of this study was to assess the effect of folic acid (FA) supplementation on colitis-associated colorectal cancer (CRC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model.

METHODS: Mice were fed a chow containing 2 mg/kg FA at baseline and randomized after the first DSS treatment to receive 0, 2, or 8 mg/kg FA chow for 16 weeks. Colon tissue was collected for histopathological evaluation, genome-wide methylation analyses (Digital Restriction Enzyme Assay of Methylation), and gene expression profiling (RNA-Seq).

RESULTS: A dose-dependent increase in the multiplicity of colonic dysplasias was observed, with the multiplicity of total and polypoid dysplasias higher (64% and 225%, respectively) in the 8 mg FA vs. the 0 mg FA group ( p < 0.001). Polypoid dysplasias were hypomethylated, as compared to the non-neoplastic colonic mucosa ( p < 0.05), irrespective of FA treatment. The colonic mucosa of the 8 mg FA group was markedly hypomethylated as compared to the 0 mg FA group. Differential methylation of genes involved in Wnt/β-catenin and MAPK signaling resulted in corresponding alterations in gene expression within the colonic mucosa.

CONCLUSIONS: High-dose FA created an altered epigenetic field effect within the non-neoplastic colonic mucosa. The observed decrease in site-specific DNA methylation altered oncogenic pathways and promoted colitis-associated CRC.

Original languageEnglish
Article number2949
Issue number11
StatePublished - Apr 27 2023


  • colitis
  • colon
  • folic acid
  • methylation
  • tumorigenesis


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