Aging, Environment, & DiseaseDNA Methylation and Hydroxymethylation

Risk for Colorectal Cancer is Increased by Obesity-related Gene Expression Changes

Colorectal cancer and obesityColorectal cancer is an age-related disease traditionally seen in populations over the age of 50. In recent years, colorectal cancer has become more prevalent in younger individuals, and obesity is thought to be a major risk factor. However, the molecular mechanisms underlying this increased risk remains unclear. Since DNA methylation changes have been noted to occur  in both colorectal cancer and obesity[1], [2], Li et al 2018 used a high-fat diet in mice to investigate whether obesity drives changes in DNA methylation that could lead to gene expression changes and increase the risk for colorectal cancer[3]. The authors also wanted to determine if weight loss could reverse obesity-related changes in gene expression and thereby reduce the risk of colorectal cancer.

The study found that obesity-related differences in gene expression overlap with colorectal cancer-related gene expression changes.  Moreover, obesity-driven DNA methylation alterations at distal regulatory regions of genes related to metabolism and cellular proliferation, coincide with transcriptional changes seen in colon tumorigenesis. With a low-fat diet, the cells of the colonic epithelium favor short-chain fatty acids, such as butyrate, as an energy source. When mice are put on a high-fat diet, the colonic epithelium begins to decrease expression of genes related to short-chain fatty acid metabolism, such as Acyl-CoA synthetases and Acyl-CoA dehydrogenase. At the same time, expression of genes involved in long-chain fatty acid metabolism are increased, including Very Long-chain Acyl-CoA synthetase. The use of long-chain fatty acids as a main energy source in the colonic epithelium can increase the risk for cancer by promoting stem cell functions[4]. In support of increased risk for tumorigenesis, a decrease in expression of genes related to transcriptional regulation, including genes that are part of NK-kB, TGF-β, JAK/STAT, and mTORC1 signaling pathways was found in the colonic epithelium of aged obese mice.

The authors also wanted to know if the epigenetic and gene expression changes in metabolism and cellular proliferation brought on by obesity would persist after weight loss. Li et al found that after short-term weight loss of 5 weeks, DNA methylation and gene expression profiles had not reverted to the profiles of normal weight mice. This was true even though the mice were no longer obese after 5 weeks on a low-fat diet. These results indicate that short-term weight loss might not lower the risk of colorectal cancer related to a high-fat diet. On the other hand, after a long-term weight loss of 28 weeks the gene expression of colonic epithelium cells returned to a non-obese state.

The risk of colorectal cancer in obese mice is increased due to epigenetic and gene expression changes related to consuming a high-fat diet. These changes in gene expression may stimulate colorectal stem cells to proliferate uncontrollably, a hallmark of cancer. The author’s results also show that losing weight does not necessarily decrease a person’s risk for colorectal cancer. Instead, sustained weight loss of several months is required to decrease the risk of colorectal cancer.


Original Article

  1. L. R et al., “Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer.,” Cell Reports, vol. 22, Jan. 2018.


  1. V. V. Lao and W. M. Grady, “Epigenetics and Colorectal Cancer,” Nat Rev Gastroenterol Hepatol, vol. 8, no. 12, pp. 686–700, Oct. 2011.
  2. B. R et al., “Weight loss after gastric bypass surgery in human obesity remodels promoter methylation.,” Apr. 2013.
  3. L. R et al., “Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer.,” Cell Reports, vol. 22, Jan. 2018.
  4. S. Beyaz et al., “High fat diet enhances stemness and tumorigenicity of intestinal progenitors,” Nature, vol. 531, no. 7592, pp. 53–58, Mar. 2016.
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Aaron Barnett

Aaron Barnett