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Obesity transmits epigenetic signals for colorectal cancer - mtwalsh01 - 04-02-2014

Obesity has become so widespread in westernised countries that it has reached epidemic levels. It is associated with higher risk of multiple life-threatening diseases including cancer. Now a new study led by researchers from the National Institute of Environmental Health Sciences (NIEHS), part of NIH, suggests that obesity rather than diet is the major driver of genetic changes in the colon which can lead to colorectal cancer. The study is published online today in the journal Cell Metabolism.

Colorectal cancer is globally the third most common cancer and ranks second in causing cancer deaths. Obesity is the target of major public health campaigns worldwide but incidence keeps increasing. For example, the majority of Americans are now considered overweight or obese. Obesity is a risk factor for diseases ranging from cardiovascular disease and diabetes to cancer. The association of obesity with colorectal cancer is stronger in men than in women. In the present study, the researchers assumed that the contributing factors linking obesity and colorectal cancer would be complex and that relative effects of diet, weight gain and obesity need to be considered carefully.

The study employed a transgenic mouse model containing a human version of a gene called NAG-1 (non-steroidal anti-inflammatory drug (NSAID)-activated gene-1) and made comparisons to mice who lacked this gene. NAG-1 protects against colon cancer in other rodent studies. The researchers fed some mice in both groups a high-fat diet in which 60% of calories came from fat and some mice a low-fat diet in which 10% of calories came from diet. The NAG-1 positive mice did not gain weight on the high-fat diet while the wild type mice lacking NAG-1 became obese. This provided a method for observing relative effects of diet and obesity.

The researchers observed changes in enhancer regions of genes in colonic epithelial cells. Enhancer regions are involved in regulation of gene expression. Enhancers are influenced by a group of proteins called histones, whose activity is dependent on patterns of acetylation. Study results showed that high-fat diet could cause alterations in the histone acetylation patterns and enhancer landscape of colonic epithelial cells that resembled changes that occur in colorectal cancer. However, these changes only occurred in the wild type, obese mice not in the NAG-1, thin mice. This suggests that obesity rather than diet per se is the relevant driver of the epigenetic changes associated with development of colorectal cancer.

The next step for the research team is to find out how and why obesity drives development of colorectal cancer. They have identified fat cells as likely candidates for triggering colonic tumour growth but there are other possibilities. Dr Paul Wade, senior author on the paper, said: "Once we identify the signalling pathways and understand how the signal is transduced, we may be able to design ways to treat colorectal cancer in obese patients."

Sources:

Li R, Grimm SA, Chrysovergis K, Kosak J, Wang X, Du Y, Burkholder A, Janardhan K, Mav D, Shah R, Eling TE, Wade, PA. 2014. Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression. Cell Metab; doi:10.1016/j.cmet.2014.03.012 [Online 1 April 2014].

Press release: NIH/National Institute of Environmental Health Sciences; available from http://www.eurekalert.org/pub_releases/2014-04/nioe-opt033114.php