Publication Date

1-19-2024

Journal

Cancer Research Communications

DOI

10.1158/2767-9764.CRC-23-0356

PMID

38259096

PMCID

PMC10798135

PubMedCentral® Posted Date

1-19-2024

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Animals, Humans, Mice, Carcinogenesis, Cell Transformation, Neoplastic, Diet, Epigenesis, Genetic, Folic Acid, Intestinal Neoplasms, Cyclin-Dependent Kinase Inhibitor p16

Abstract

The extent to which non-genetic environmental factors, such as diet, contribute to carcinogenesis has been long debated. One potential mechanism for the effects of environmental factors is through epigenetic modifications that affect gene expression without changing the underlying DNA sequence. However, the functional cooperation between dietary factors and cancer-causing epigenetic regulation is largely unknown. Here, we use a mouse model of age-dependent p16 epimutation, in which the p16 gene activity is directly controlled by promoter DNA methylation. We show p16 epimutation is modulated by folate and cofactors in dietary supplementation, which leads to increased colon cancer risk. Importantly, our findings provide functional evidence concerning the safety of folate fortification in the general population.

SIGNIFICANCE: Our study demonstrates that dietary folate and cofactors modulate tumor-suppressor gene methylation to increase intestinal tumorigenesis. Our findings highlight the need for monitoring the long-term safety of folate fortification in high-risk individuals.

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