DNC News

Epigenetics and cancer:

Jacob Schor, ND

July 11, 2007

 

I sometimes begrudge how easily I devoted memory cells in my younger years to things which now prove to be of little use. Old phone numbers take up space that would be better devoted to new numbers or passwords.

 

Case in point is the memory space set aside in Biology 101 forty years ago to that French guy Lamarck and his discredited theory.

 

 

Portrait of Jean-Baptiste Lamarck

Jean-Baptiste Lamarck 1744-1829   Gregor Mendel 1822-1844

 

Lamarck expounded a classic theory, commonly referred to as the theory of adaptation, that characteristics acquired by an organism through adaptation during its lifespan would be passed on to its offspring. A simple example is that if you exercised a lot and had big muscles, your kids would have big muscles. Gregor Mendel with his pea plant and his theory that characteristics were inherited through genes had totally supplanted Lamarck's ideas. If memory serves me correctly, only a few Stalinist Russian scientists still clung to Lamarck's theory and they were had already been shot.

 

It's time to dig out Lamarck's theory from the rubbish bin. New research on genetics suggests that although Lamarck was wrong, he was not totally wrong.

 

Epigenetics:

Over the last 15 years researchers have added a great deal to the understanding of biochemical mechanisms and what is going on inside cells. While the public debates evolution versus creationism, scientists continue to move our understandings forward. The term epigenetic is showing up in cancer literature that describes chemical modifications to how genes function. These modifications aren't changes in the gene itself but are ‘on top of the gene' literally what the term epigenetic means.

 

For years, we have thought of cancer as a disease caused by genes that have undergone mutations that trigger the growth of cancer cells. It now looks more complicated than that. Epigenetic research suggests that many cancers may not be caused by mutations in genes but by chemical modifications that change how the genes function.

 

Epigenetic modifications influence gene expression and can play a pivotal role in cancer. For example, tumor suppressor gene, which normally regulates cell growth and death, can be shut down by an epigenetic modification, rather than by a change in the gene itself.

 

Two types of epigenetic modifications:

There are two main epigenetic changes that have been studied in relation to cancer. Both changes have to do with how the DNA is packed into the cell's nucleus. Inside the nucleus of a cell, DNA is coiled tightly around little protein beads called histones. Methyl groups, little chemical clusters, can stick to particular sites on the DNA and methylate the DNA. These methyl groups stuck to the DNA strand are like little book marks that send specific messages to the cells expression of the information in the DNA. DNA methylation can turn genes on or off and either get them to or prevent them from being expressed. Changes in histones can also cause epigenetic effects. Various chemicals can hook onto those histone beads and alter how the DNA coils. If the DNA is coiled loosely, more methylation occurs. In all of these epigenetic events, the genes are unchanged but whether they are expressed in the cell change.

 

 

Where it gets interesting:

Epigenetic modifications can be passed on to offspring, that is, they can be inherited. The gene stays the same but whether it is expressed can be changed in future generations. Randy Jirtle at Duke University has done some interesting things with Agouti mice. The agouti gene gives mice yellow fur, and a strong predisposition to obesity, cancer and diabetes. Jirtle fed pregnant agouti mice vitamin B-12, folic acid, choline and Betaine. This is pretty much the same formula naturopathic doctors often prescribe in order to lower homocysteine levels. These nutrients are collectively referred to as ‘methyl donors'and they are often used to promote methylation. The apparently bookmarked the agouti gene and prevented its expression.

Most of the offspring of the mice fed these diets rich in methyl donors were born with brown coats and did not become fat or develop the expected diseases. The control group of mice not fed the methyl donor enriched diet were born with yellow fur and got sick and died as expected. [i]

 The mothers given the vitamin supplements gave birth to darker pups than those on a standard diet

The mothers given the vitamin supplements gave birth to darker pups than those on a standard diet

 

 

Another example of epigenetic action is the chemical lunasin. Dr. Benito de Lumen at the University of California, Berkeley first identified this chemical in soy in 1999 and since then has found it in barley and wheat. Lunasin prevents skin cancer in mice through an epigenetic mechanism. Lunasin's mechanism is different from the other cancer fighting chemicals found in soy. Lunasin makes its way into the nucleus of cancer cells and changes the histones in a way that changes the way DNA unwinds. It does not change the DNA sequence. These epigenetic change kills newly transformed cancer cells while leaving the normal cells unaffected. [ii] A paper published in May 2007 that describes isolation of lunasin from wheat reaffirms several earlier papers that suggest the action is due to acetylation of the histones. [iii]

 

The very concept of epigenetics is still so new that it is hard to fathom. It does suggest though that environmental influences can be passed to offspring without actual changes in genetic code. Followers of the Price Pottinger foundation no doubt will be writing me to say that Pottinger proved this with his cats years ago, so perhaps we can't say this is all new.

 

The bottom line, old Lamarck may have been wrong but he wasn't a hundred percent wrong. Genetics isn't as simple as Gregor thought. Reading through this epigenetic reserach suggests that it is time for me to dredge up those memory files saved 40 years ago and revise them.  The truth is that there are acquired traits that may be passed down to offspring in a manner independent of genes. This information and the understanding of epigenetics may play an important role in preventing and treating cancer in future years. The current state of the science strongly suggests that diet and nutrition can have a lasting effect on genetic expression stretching into future generations.

 

[i] Mol Cell Biol. 2003 Aug;23(15):5293-300. Click here to readks

Transposable elements: targets for early nutritional effects on epigenetic gene regulation.

Waterland RA , Jirtle RL .

Department of Radiation Oncology, Duke University Medical Center , Durham , NC 27710 , USA .

Early nutrition affects adult metabolism in humans and other mammals, potentially via persistent alterations in DNA methylation. With viable yellow agouti (A(vy)) mice, which harbor a transposable element in the agouti gene, we tested the hypothesis that the metastable methylation status of specific transposable element insertion sites renders them epigenetically labile to early methyl donor nutrition. Our results show that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B(12), choline, and betaine alter the phenotype of their A(vy)/a offspring via increased CpG methylation at the A(vy) locus and that the epigenetic metastability which confers this lability is due to the A(vy) transposable element. These findings suggest that dietary supplementation, long presumed to be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic gene regulation in humans.

PMID: 12861015 [PubMed - indexed for MEDLINE]

 

[ii] Nutr Rev. 2005 Jan;63(1):16-21.

Lunasin: a cancer-preventive soy peptide.

de Lumen BO .

Department of Nutritional Sciences and Toxicology, University of California , 231 Morgan Hall, Berkeley , CA 94720-3104 , USA . nitto@nature.berkeley.edu

Lunasin is a novel, cancer-preventive peptide whose efficacy against chemical carcinogens and oncogenes has been demonstrated in mammalian cells and in a skin cancer mouse model. Isolated and characterized in soy, lunasin peptide is also documented in barley. Lunasin is found in all of the genotypes analyzed from the US soy germ plasm collection and in commercially available soy proteins. Pilot studies show that lunasin is bioavailable in mice and rats when orally ingested, opening the way for dietary administration in cancer prevention studies. Lunasin internalizes into mammalian cells within minutes of exogenous application, and localizes in the nucleus after 18 hours. It inhibits acetylation of core histones in mammalian cells. In spite of its cancer-preventive properties, lunasin does not affect the growth rate of normal and established cancer cell lines. An epigenetic mechanism of action is proposed whereby lunasin selectively kills cells being transformed or newly transformed by binding to deacetylated core histones exposed by the transformation event, disrupting the dynamics of histone acetylation-deacetylation and leading to cell death.

PMID: 15730231 [PubMed - indexed for MEDLINE]

 

[iii] Cancer Lett. 2007 May 2; [Epub ahead of print]

The cancer preventive peptide lunasin from wheat inhibits core histone acetylation.

Jeong HJ , Jeong JB , Kim DS , Park JH , Lee JB , Kweon DH , Chung GY , Seo EW , de Lumen BO .

College of Natural Sciences , Andong National University , Andong, Republic of Korea .

Lunasin is a unique 43-amino acid cancer preventive peptide initially reported in soybean and barley and has been shown to be chemopreventive in mammalian cells and in a skin cancer mouse model against oncogenes and chemical carcinogens. We report here the core histone H3- and H-acetylation inhibitory properties of lunasin from wheat, a new source of the peptide and from the livers of rats fed with lunasin-enriched wheat (LEW) to measure bioavailability. A non-radioactive histone acetyl transferase assay was used to measure inhibition of core histone acetylation. The presence of lunasin in wheat was established by Western blot and identified by liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS). Lunasin isolated from wheat seeds at different stages of development inhibited core histone H3 and H4 acetylation in a dose-dependent manner. Lunasin extracted from liver of rats fed with lunasin-enriched wheat (LEW) also inhibited histone acetylation confirming that the peptide is intact and bioactive. The amounts of lunasin in the developing seeds and in the rat liver correlated extremely well with the extent of inhibition of core histone acetylation.

PMID: 17481808 [PubMed - as supplied by publisher]

 


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