DNA Methylation, Diet and Cancer Prevention

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DNA Methylation, Diet and Cancer Prevention

• Nutritional Science Research Group
• Division of Cancer Prevention

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DNA Methylation Influences Cancer Processes
DNA Repair
Hormonal Regulation
Carcinogen Metabolism
DNA Methylation
Differentiation
Cell Cycle
Apoptosis
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Bioactive Food Components in the DNA Methylation
Process
Nutrients
Polymorphisms
SAH
SAM
CpG
Me-CpG
DNA Methyltransferase
DNA Demethylation
Nutrients?
Tumor
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Dietary Factors Known to Influence DNA Methylation
Alcohol Arsenic Choline
Coumestrol Equol Fiber Folate Genistein
Methionine Selenium Vitamin A
Zinc
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Dietary Folate Deficiency Causes Hypomethylation
in Human Lymphocytes
100
1- 3H-Methyl Acceptance ()
50
0
6
69
Day of Depletion
Jacob et al J. Nutr. 1281204, 1998
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Folate Depletion Alters DNA Methylation
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Relative Amount of Methylated DNA in H-cadherin
CpG Island
25
0
- Folate
Folate
Adapted from Jhaveri et al. Mol Pharmacol (2001)
601288-1295
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LTR Hypomethylated
LTR Hypermethylated
Maternal Supplements with zinc methionine
betaine choline, folate B12
Yellow Mouse
Agouti Mouse
High risk cancer, diabetes, obesity reduced
lifespan
Lower risk of cancer, diabetes, obesity and
prolonged life
Cooney J. Nutr. 2002 (In Press)
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Sensitization by 5-Aza-deoxycytidine of Leukemia
Cells to Differentiation by Retinoic Acid
Untreated Retinoic Acid 5-AZA 5-AZA Retinoic
Acid
40 -
30 -
Differentiation Ratio
20 -
10 -
SN-1
KOCL33
KOCL51
Nitsu, et al. British Journal of Hematology 112
315, 2001.
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Goals of This Concept

• To promote novel research on the role of
  bioactive food components in DNA methylation
  processes involved with
• cell vulnerability to cancer
• and/or
• cellular responsiveness to prevention

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Approach
Encourage collaboration between nutrition and DNA
methylation experts to study bioactive food
components with cancer preventative properties
To examine key epigenetic events involved in
cancer processes
To establish linkages between methylation pattern
and tumor incidence/behavior
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Model Application Might Include
Bioactive Food Component
Transgenic or KO Mice (DNA Mtase, MTHFR)
Combined with DNA Methylation Inhibitors
Transfection (Me-CpG promoter)
DNA Methylation Targets
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Overarching Issues

• How do bioactive food components regulate DNA
  methylation processes for cancer prevention?
• Can bioactive food components alter DNA
  methylation and restore gene function?
• Can bioactive food components circumvent or
  compensate for genes and pathways that are
  altered by DNA methylation?

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Mechanism for Concept

• To foster novel and innovative approaches to
  determine interactions between DNA Methylation
  and Diet
• Individual Research Project Grants (R01)
• Exploratory/Developmental Grants (R21s)
• Supplement to Existing Grants

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Support for the RFA Concept

• NCI Nutrition Implementation Report (1999)
• Trans-HHS Workshop Diet, DNA Methylation
  Processes and Health (August 2001)
• National Cancer Institutes Extraordinary
  Opportunities (2003)

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Proposed Total Budget (Million-Direct and
Indirect)(7 to 10 Grants)
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FY01 Extramural Portfolio Analysis
Cancer (RPG) 1,845
100.0 Cancer Prevention 756 252
13.7 Nutrition 631 166 9.0 Nutrition
Cancer Prevention 199 64 3.5 DNA
Methylation 85 22
1.2 Nutrition DNA Methylation 8 5
0.3
Data courtesy of the Research Analysis and
Evaluation Branch, DEA/NCI Includes 1 P01 for
3.7 M