Folate deficiency and cancer risk

Folate, also known as vitamin B9, is a water-soluble vitamin with high biological activity and plays an important role in health.

Folate deficiency directly and indirectly affects the metabolism of cells in the body, causes many disorders and can lead to impaired human growth and development. In particular, when there is a deficiency of folic acid in the human body, the risk of forming and developing some cancers increases.

1.Role of folate

Folate is involved in the growth and division of all types of human, animal, plant and bacterial cells.

Folate acts as a coenzyme in reactions involving the transport of a methyl group (CH3) from one compound to another, essential for cell synthesis and growth:

– Synthesize amino acids methionine, histidine and serine.

– Convert the amino acid phenylalanine to tyrosine.

– Form the heme group of hemoglobin.

– Synthesize purines and pyrimidines – raw materials for the synthesis of DNA and RNA for cells.

– Generate catecholamine neurotransmitters (dopamine, adrenaline, serotonin) in the brain.

– Convert niacin to its excreted form.

In humans, folate deficiency leads to serious diseases, the most important of which are neural tube defects, macrocytic anemia, accelerated arteriosclerosis, central nervous system dysfunction and development of certain types of cancer.

2. Folate and cancer risk

Due to folate’s special role in growth, cell division and nucleic acid synthesis, cell division regulation, folate excess and deficiency are strongly associated with cancer development.

Published scientific data that meta-analysis of the results of studies (cohorts and case-control studies) evaluating the effectiveness of increased folic acid intake in relation to reduction of cancer risk have shown that with a deficiency of folic acid in the human body, the risk of forming and developing certain cancers increases (eg, cancers of the colon, breast, ovary, uterus, lung, pancreas and other diseases).

Epidemiological and nutritional observations indicate that the consumption of fresh vegetables rich in folic acid has a protective effect against tumor formation.

2.1 DNA methylation mechanism

The role of folic acid in nucleic acid metabolism is based on the participation of its coenzymes in the formation of methionine from homocysteine – the substrate for the synthesis of S-adenosylmethionine, which is involved in DNA methylation.

DNA methylation plays an important role in regulating gene expression

On the other hand, histone methylation is responsible for the chromosomal structure. Excessive methylation in the regulatory portion of most genes shuts down their transcription. The expression level of a given gene is correlated with the amount of methylated DNA, the higher the level of methylation, the weaker its expression. Abnormal levels of DNA methylation in genes encoding proteins involved in cell cycle control and regulation (eg, suppressor genes) or apoptosis can lead to neoplastic transformation.

In cells of many cancers, increased or decreased CpG sequence methylation is found in the promoter regions of genes whose protein products are involved in cell cycle regulation and cell cycle regulation and cell death process. Changes in intracellular DNA methylation levels are also observed during the formation and development of atherosclerosis, as well as during the aging process of the organism.

The preventive effect of folic acid is related to the participation in the synthesis of nucleic acids and S-adenosylmethionine and in DNA methylation. Low levels of folic acid lead to reduced or hypermethylated DNA, and this affects the expression of repressor genes that activate proto-oncogenes into cancer, resulting in decreased cell DNA stability.

Although many studies have shown that folic acid plays an important role in the prevention of certain types of cancer, there is still uncertainty about the beneficial effects of high doses, especially in people at risk for cancer. Recently, studies have emerged showing that taking folic acid supplements and consuming foods rich in this compound can accelerate the growth of colorectal tumors such as colon, larynx, prostate and breast cancers.

Folate deficiency can cause cancerous transformation, moderate amounts (supplementation, fortification of food products) can inhibit it, but even high doses of folic acid can accelerate growth of cancer. It is believed that excess folic acid causes DNA hypermethylation, which can lead to the inactivation of repressor genes responsible for appropriately controlling cell division.

2.2 Mechanism

Homocysteine (Hcy) is a toxic, non-sulfur amino acid found in the mutual conversion pathway of two amino acids: methionine and cysteine in which folate participates.

Folate has an inverse relationship with Hcy: low levels of folate lead to accumulation of Hcy in the blood plasma and vice versa. Elevated plasma homocysteine has also been shown to be strongly associated with cancer. Folate is needed to convert dUMP to thymidine monophosphate.

With folate deficiency, dUMP accumulates leading to an imbalance in the deoxyribonucleotide group. Thus, there is an over-incorporation of uracil into DNA instead of thymine, which is usually corrected by the enzyme uracil DNA glycosylase, which removes the misincorporated uracil from the DNA strand. When folate levels are disturbed (due to increased Hcy levels), DNA glycosylase cannot cope with the burden of DNA repair. This condition leads to chromosomal damage, which can then lead to malignant transformation in the cell.

Furthermore, excision repair of uracil moieties separated by 12 base pairs can lead to double-strand breaks, which can increase DNA instability because DNA supercoiling and chromosomal remodeling are relaxed, both of which can cause an increase in malignant transformation.

References:

1.  Barbara, Bowman, and R. M.Russel, Present Knowledge in Nutrition. Washington DC: ILCL Press, 2001.
2. “Folic acid in physiology and pathology | Postępy Higieny i Medycyny Doświad”. https://phmd.pl/resources/html/article/details?id=7459&language=en (November 2022).
3. T. Hasan, R. Arora, A. K. Bansal, R. Bhattacharya, G. S. Sharma, và L. R. Singh, “Disturbed homocysteine metabolism is associated with cancer”, Exp Mol Med, vol 51, p.h 2, p. 21, month February 2019, doi: 10.1038/s12276-019-0216-4.

Article source: Nutrition Research and Development Institute (https://inrd.vn/)

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