Dietary Compounds that Affect the Epigenome Tested for Cancer Prevention
Division of Cancer Prevention
The list of known genetic mutations that can lead to cancer grows daily. In addition, scientists have discovered another layer of complexity driving abnormal gene expression in the disease: epigenetics. Epigenetic changes are changes to a chromosome’s structure that do not change the genetic sequence itself, but nonetheless change the way genes are expressed within cells.
For example, a type of epigenetic change – called histone acetylation – controls whether or not a gene can be transcribed into RNA. If too many acetyl groups are removed by enzymes called histone deacetylases (HDACs), the DNA becomes wound too tight and cannot physically be reached by a cell’s transcription factors (proteins that control the translation of DNA into RNA). If this complex sequence of events results in “silencing” a tumor suppressor gene, the result can be a cancer cell.
A group of compounds called HDAC inhibitors, which stop the removal of acetyl groups, have shown promise for the treatment of several cancer types. Roderick Dashwood, Ph.D., director of the Cancer Chemoprotection Program at the Linus Pauling Institute at Oregon State University, is exploring the use of HDAC inhibitor compounds found in foods as potential chemopreventive agents for colorectal cancer.
His work so far has concentrated primarily on sulforaphane, a compound found in cruciferous vegetables such as broccoli. Researchers had previously focused on sulforaphane as an inducer of cells’ natural detoxification enzymes, which can add polar groups to carcinogens and help remove them from the cells.
“In some studies, carcinogens were given to animals and then followed later by doses of sulforaphane. Tumor suppressor effects were still noted,” Dr. Dashwood explained. “If the entire protection was related to induction of detoxification enzymes and enhanced carcinogen excretion, that wouldn’t explain why, in an animal that has already been exposed to a colon carcinogen, sulforaphane would still be effective.” He added, “When we treated colon cancer cells with sulforaphane, we saw certain genes being turned on in a way that resembled the effects of some HDAC inhibitor drugs, such as vorinostat,” which is approved for the treatment of cutaneous T-cell lymphoma.
In a previous study*, Dr. Dashwood and his colleagues first showed that metabolites of sulforaphane act as HDAC inhibitors and can re-activate a gene called p21, which arrests the cell cycle. They also showed that sulforaphane in the diet suppressed colon tumor formation in a mouse model and that the compound both increased acetylation of the histones and expression of p21.
In a human pilot study, a single large serving of broccoli sprouts – a food naturally high in glucoraphanin, the precursor of sulforaphane – was enough to cause significant HDAC inhibition as measured in the participants’ peripheral blood mononuclear cells, within 3 hours after eating the broccoli sprouts.
With NCI funding **, Dr. Dashwood’s research team is currently expanding their studies of sulforaphane and other potential dietary HDAC inhibitors. In cell cultures, Dashwood’s team is investigating which individual HDACs (HDAC1, HDAC2, etc.) control the expression of p21 and which are affected either by sulforaphane or organosulfur compounds from garlic, including the metabolite allyl mercaptan.
However, a detailed understanding of the molecular pathways affected by dietary HDAC inhibitors is needed before moving to clinical trials, Dr. Dash-wood cautioned. “We still don’t really know precisely what group of genes and downstream pathways specific HDACs are regulating in colon cancer cells versus prostate cancer cells.” By studying weaker dietary HDAC inhibitors, “we hope to provide new insights into ways to avoid serious side effects while maintaining therapeutic efficacy,” he added.
NCI Program Director Sharon Ross, Ph.D., M.P.H., commented, “NCI’s Division of Cancer Prevention believes this project is significant because it will enhance our understanding of how dietary factors in broccoli and garlic, working through epigenetic mechanisms, may increase the expression of tumor suppressor genes, thereby halting aberrant proliferation and/or inducing death of abnormal cells. These studies should inform future dietary intervention trials for cancer prevention.”
*Myzak MC, Karplus PA, Chung FL, Dashwood RH. A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Research, August 15, 2004; 64(16):5767-74.
**Grant Number: 1R01CA122959-1