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Research Project: Metabolic and Epigenetic Regulation of Nutritional Metabolism

Location: Children's Nutrition Research Center

Title: Dietary folate and cofactors accelerate age-dependent p16 epimutation to promote intestinal tumorigenesis

item YANG, LI - Children'S Nutrition Research Center (CNRC)
item PEERY, ROBERT - Children'S Nutrition Research Center (CNRC)
item FARMER, LEAH - Children'S Nutrition Research Center (CNRC)
item GAO, XIA - Children'S Nutrition Research Center (CNRC)
item ZHANG, YIQUN - Baylor College Of Medicine
item CREIGHTON, CHAD - Baylor College Of Medicine
item ZHANG, LANJING - Rutgers University
item SHEN, LANLAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Cancer Research Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/3/2024
Publication Date: 1/19/2024
Citation: Yang, L., Peery, R.C., Farmer, L.M., Gao, X., Zhang, Y., Creighton, C.J., Zhang, L., Shen, L. 2024. Dietary folate and cofactors accelerate age-dependent p16 epimutation to promote intestinal tumorigenesis. Cancer Research Communications. 4(1):164-169.

Interpretive Summary: Over the past decades, researchers have been debating how much our environment, especially factors like diet, contribute to the development of cancer. One way these factors might influence cancer is through changes in gene activity that do not involve altering the DNA sequence itself, known as epigenetic modifications. However, we haven’t fully understood how dietary factors and cancer-related epigenetic changes work together. In this study using mice, the researchers focused on a specific gene (p16) involved in controlling cell growth and found that its epigenetic changes were influenced by the intake of folate and related nutrients in the diet. These changes, in turn, increased the risk of colon cancer. Importantly, the study suggests that fortifying foods with folate, a common practice to prevent birth defects, may have unintended consequences in certain situations. The findings emphasize the importance of carefully monitoring the long-term safety of folate fortification, especially in individuals with a higher risk of cancer.

Technical 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.