Inflammation-induced DNA methylation of DNA polymerase gamma alters the metabolic profile of colon tumors.

BACKGROUND

Inflammation, metabolism, and epigenetic modulation are highly interconnected processes that can be altered during tumorigenesis. However, because of the complexity of these interactions, direct cause and effect during tumorigenesis have been difficult to prove. Previously, using a murine model of inflammation-induced colon tumorigenesis, we determined that the promoter of the catalytic subunit of DNA polymerase gamma () is DNA hypermethylated and silenced in inflammation-induced tumors, but not in non-inflammation-induced (mock) tumors, suggesting that inflammation can induce silencing of through promoting DNA methylation during tumorigenesis. is the only mitochondrial DNA polymerase and mutations in cause mitochondrial diseases in humans. Because of the role of mitochondria in metabolism, we hypothesized that silencing of in inflammation-induced tumors would result in these tumors having altered metabolism in comparison to mock tumors.

METHODS

Inflammation-induced and mock colon tumors and colon epithelium from a mouse model of inflammation-induced colon tumorigenesis were assayed for alterations in expression, mitochondria, and metabolism. Organoids derived from these tissues were used to study the direct effect of loss of on mitochondria and metabolism.

RESULTS

We demonstrate that inflammation-induced tumors with reduced expression have decreased mitochondrial DNA content and numbers of mitochondria compared to normal epithelium or mock tumors. Tumoroids derived from mock and inflammation-induced tumors retained key characteristics of the original tumors. Inflammation-induced tumoroids had increased glucose uptake and lactate secretion relative to mock tumoroids. shRNA-mediated knockdown of in mock tumoroids reduced mtDNA content, increased glucose uptake and lactate secretion, and made the tumoroids more resistant to oxidative stress.

CONCLUSIONS

These results suggest that inflammation-induced DNA methylation and silencing of plays an important role in the tumorigenesis process by resulting in reduced mitochondria levels and altered metabolism. An enhanced understanding of how metabolism is altered in and drives inflammation-induced tumorigenesis will provide potential therapeutic targets.