# Presentation: 380047

## DNA Methylation, Diet and Cancer Prevention

**Nutritional Science Research Group**
**Division of Cancer Prevention**

## DNA Methylation Influences Cancer Processes

**DNA Repair**

**Hormonal Regulation**

**Carcinogen **
**Metabolism**

** ****Apoptosis**

**Differentiation**

**Cell Cycle**

**DNA**
**Methylation**

## Bioactive Food Components in the DNA Methylation Process

**Bioactive Food Components in the DNA Methylation Process**

**DNA Methyltransferase**** **

**DNA Demethylation**

**SAM**

**Nutrients**

** ****Nutrients?**

**CpG**

**Me-CpG**

**SAH**

- Tumor

- Polymorphisms

## Dietary Factors Known to Influence DNA Methylation

**Alcohol                  Arsenic**
**Choline                  Coumestrol**
**Equol ****	****Fiber**
**Folate****	****Genistein **
**Methionine           ****	****Selenium**
**Vitamin A             ****	****Zinc**

## Dietary Folate Deficiency Causes Hypomethylation in Human Lymphocytes

**1- ****3****H-Methyl Acceptance (%)**

**100**

**50**

**0**

**Day of Depletion**

**6**

**69**

**Jacob et al J. Nutr. 128:1204, 1998**

**Dietary Folate Deficiency Causes Hypomethylation in Human Lymphocytes**

## Folate Depletion Alters 

**Folate Depletion Alters **
**DNA Methylation**

**Relative Amount of Methylated DNA in**
**H-cadherin CpG Island**

**+****Folate**

**50**

**25**

**0**

**- ****Folate**

## Yellow Mouse

**Yellow Mouse**

**Agouti Mouse**

- Cooney  J. Nutr. 2002 (In Press)

**Maternal Supplements **
**with**
**zinc**
**methionine **
**betaine**
**choline,**
**folate**
**B****12**

**High risk cancer, diabetes, obesity & reduced lifespan**

**Lower risk of cancer, diabetes, obesity and prolonged life**

**LTR Hypomethylated**

**LTR Hypermethylated**

## Sensitization by 5-Aza-deoxycytidine of Leukemia Cells to Differentiation by Retinoic Acid 

**Sensitization by 5-Aza-deoxycytidine of Leukemia Cells to Differentiation by Retinoic Acid **

- 20 -

- 40 -

- 10 -

- 30 -

**Untreated**
**Retinoic Acid**
**5-AZA**
**5-AZA + Retinoic Acid**

**SN-1**

**KOCL33**

**KOCL51**

**Differentiation Ratio**

*Nitsu, et al. British Journal of Hematology 112: 315, 2001.*

## 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**

## Approach

**Encourage collaboration between nutrition and DNA methylation experts to study bioactive food components with cancer preventative properties**

**Approach**

**To establish linkages between methylation pattern and tumor incidence/behavior**

## Bioactive Food Component

**Model Application Might Include**

**Transgenic or KO Mice **
**(DNA Mtase, MTHFR)**

**Bioactive Food Component**

**Combined **
**with DNA Methylation Inhibitors**

**Transfection**
**(Me-CpG promoter)**

**DNA Methylation**
** ****Targets**

## 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?**

## Mechanism for Concept

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

## Support for the RFA Concept:

**NCI Nutrition Implementation Report (1999)**
**Trans-HHS Workshop “Diet, DNA Methylation Processes and Health” (August 2001)**
** ****National Cancer Institute’s Extraordinary Opportunities (2003)**

## Proposed Total Budget (Million-Direct and Indirect)(7 to 10 Grants)

|  |  |  |  |  |
| --- | --- | --- | --- | --- |
|  |  |  |  |  |

| 
Year
 | 
2004
 | 
2005
 | 
 2006 | 
 2007 | 
Total
 |
| --- | --- | --- | --- | --- | --- |
| Budget
 |  $ 2.5 |  $ 2.55 |  $ 2.6 |  $ 2.65 |  $ 10.3 |

## 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**