Editors' ChoiceEpigenetics

Obesity Paves the Highway for Colon Cancer

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Science Translational Medicine  07 May 2014:
Vol. 6, Issue 235, pp. 235ec79
DOI: 10.1126/scitranslmed.3009301

Obesity raises the risk for developing colon cancer by a moderate amount—relative risk 1.09 to 1.24 times that of lean, healthy individuals—but the molecular underpinnings for this have remained a mystery. The roles of insulin, adipokines (such as leptin and adiponectin), inflammation, and metabolic signaling pathways have all been scrutinized, but no single molecule or pathway satisfactorily explains all of the risk. Dogma says that colon cancer develops from a single cell that, over time, collects sufficient mutations in enough genes to drive cancer progression. But obesity per se has not been shown to directly cause DNA sequence mutations. Now, Paul Wade’s laboratory shows that obesity increases the risk of colon cancer by altering the epigenetic landscape in colon epithelial cells. These changes interfere with the differentiated state of colon epithelial cells and prime them for proliferation—two cardinal features of oncogenesis.

The authors fed congenic mice either a low- or high-fat diet for a prolonged period in order to induce obesity and then isolated colon epithelial cells. They analyzed them using gene expression (mRNA) arrays and chromatin immunoprecipitation sequencing (ChIP-Seq) for the presence of a particular epigenetic mark on DNA binding histones: acetylation of lysine 27 on histone 3 (H3K27ac). H3K27ac is thought to mark active enhancers of gene expression. In both male and female mice, the authors identified ~1500 differentially acetylated DNA locations, most of which were more than 2 kb away from any gene’s transcriptional start site, suggesting that these regions may be gene expression enhancers. For a subset of these loci, the authors demonstrated enhancer activity.

Most strikingly, obesity induced alterations that reprogrammed the enhancer landscape in such a way that the gene expression profile of colon epithelium resembled that of human colon cancer. The most marked changes in histone acetylation occurred in DNA regions that bind to transcription factors mediating proliferation (ETS, PI3 kinase, Foxo1, and AP1) and maintenance of differentiation (Cdx2 and Klf4). The authors were able to confirm that target genes of these transcription factors were increased or decreased in accordance with the direction of histone acetylation. Interestingly, when challenged with a high-fat diet, obesity-resistant transgenic mice did not show the same alterations in the epigenetic or transcriptional landscape. The authors concluded that it is the obese state itself that pushes the epigenome toward a pro-oncogenic state, although they did not confirm whether genetically obese animals show the same changes in histone acetylation.

It remains to be seen whether the same epigenetic alterations are present in the colon epithelium of obese individuals. This work implies that premalignant colon polyps (benign adenomas) from obese individuals should develop into full-blown cancer more readily than do polyps from lean people. If so, then paying attention to the epigenome would then have profound clinical consequences for routine cancer surveillance.

R. Li et al., Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression. Cell Metab. 19, 702–711 (2014). [Abstract]

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