More on Methylation & Cancer

Food components that may reduce one’s risk of cancer are the focus of intense research. This research reaches beyond the common expectations of dietary antioxidants to the realm of cancer epigenetics, for which in-vitro evidence was introduced in the July 2007 Food, Medicine & Health column (Clemens and Cheng, 1007).

The cancer epigenome features modifications of histones, the protein components of chromatin. These modifications, such as methylation, acetylation, and phosphorylation, correlate with gene expression and genomic stability. Normal cells are characterized by unmethylated DNA and identical distribution of genetically active histone marks, such as acetylation of lysine 9 in histone 3 (H3K9ac), and methylation of lysine 4 in histone 3 (H3K4me).

In contrast, cancer cells have profoundly decreased levels of these active marks, accompanied by increased levels of gene-silencing marks. These gene-silencing marks (Ting et al., 2006) include the mono-(H3K9me), di-(H3K9me2), and tri-(HeK9me3) methylated forms of lysine 9 in histone 3 and trimethylation of lysine 27 in histone 3 (H3K27me3). In colon cancer cells with two DNA methyltransferases knocked out, H3K9me silenced the tumor suppressor gene p16 (Bachman et al., 2003).

By preserving chromatin structure and maintaining genome stability, histone methyltransferases (HMTs) and acetyltransferases (HATs) may act as tumor suppressors by retaining methylation and acetylation at specific histone residues. Changes in this tumor suppressor system could lead to neoplastic cell transformation and tumor progression by favoring cellular growth over differentiation.

A methyl-deficient diet—one lacking the major methyl donors, such as methionine, choline, folic acid, and vitamin B-12—fed to rodents represents a unique endogenous heptatocarcinogenesis model. This model demonstrates that a dietary omission of methyl groups rather than the addition of chemical carcinogens leads to tumor formation (Pogribny, et al., 2007). These observations indicate that chronic metabolic stress may drive tumor development in the liver through biochemical and molecular events mediated through epigenetic changes.

Methyl deficiency in rats initiates a sequence of events, including rapid hepatic accumulation of fat (steatosis), increased lipid peroxidation, cell death through necrosis and apoptosis, increased cell proliferation, incorporation of uracil instead of thymine into DNA, breaks in DNA strands, and increased hypomethylation within specific genes and throughout the genome. This dietary-related deficiency induces hepatic cancer in two phases: a reversible stage during which a normal liver transitions into a state of chronic liver injury, followed by an irreversible stage transitioning into tumor formation.

Interestingly, profound apoptotic cell death with increased compensatory hepatic cell proliferation, buildup of DNA lesions, increased gene expression, and DNA repair seen during the first phase is similarly noted in response to hypoxia, tamoxifen (an antiestrogen), and radiation exposure.

These observations suggest intriguing potential for risk reduction and therapeutic approaches for cancer through dietary intervention. A recently reported prospective 7-year study among approximately 80,000 Swedish women and men indicated that higher methionine consumption might reduce the risk of pancreatic cancer (Larsson et al., 2007). In a similar 9.5-year prospective study among nearly 12,000 postmenopausal women, a reduced incidence of breast cancer was detected among those with high folate intake (Ericson et al., 2007). On the other hand, recent evaluation of the impact of folic acid fortification in the United States intended to reduce the incidence of neural tube defects suggests an apparent increased rate of colorectal cancer (Mason et al., 2007) in adults, in addition to decreased incidence of neural tube defects in newborns.

The relationship between cancer and dietary intervention is complex, generating further research and controversy. While awaiting the results of future studies to confirm and extend these potentially exciting results, consumption of a rich and varied diet including folate- and methyl-rich foods should be part of the recipe for good health.

References for the studies mentioned above are available from the authors.

by Roger Clemens, Dr.P.H.,
Contributing Editor
Special Projects Advisor, ETHorn, La Mirada, Calif.
[email protected]

by Sabrina Cheng, M.D.,
FACMG
Medical Geneticist Consultant, University of California, San Francisco Cancer Risk Program
[email protected]