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Title: Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice

Author
item YU, DA-HAI - Children'S Nutrition Research Center (CNRC)
item WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)
item ZHANG, PUMIN - Baylor College Of Medicine
item SCHADY, DEBORAH - Baylor College Of Medicine
item CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC)
item GUAN, YONGTAO - Children'S Nutrition Research Center (CNRC)
item GADKARI, MANASI - Children'S Nutrition Research Center (CNRC)
item SHEN, LANLAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/5/2014
Publication Date: 9/1/2014
Citation: Yu, D., Waterland, R.L., Zhang, P., Schady, D., Chen, M., Guan, Y., Gadkari, M., Shen, L. 2014. Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice. Journal of Clinical Investigation. 124(9):3708-3712.

Interpretive Summary: Cancer has long been thought to be primarily a genetic disease, but in recent decades scientists have come to believe that epigenetic changes – which don't change the DNA sequence but how it is 'read' – also play a role in cancer. In particular DNA methylation, the addition of a methyl group (or molecule), is an epigenetic switch that can stably turn off genes, suggesting the potential to cause cancer just as a genetic mutation can. Until now, however, direct evidence that DNA methylation drives cancer formation was lacking. To test whether DNA methylation changes alone can drive cancer, we focused on p16, a gene that normally functions to prevent cancer but is commonly methylated in a broad spectrum of human cancers. We devised an approach to engineer DNA methylation specifically to the mouse p16 regulatory region (promoter). As intended, the engineered p16 promoter acted as a 'methylation magnet'. As the mice reached adulthood, gradually increasing p16 methylation led to a higher incidence of spontaneous cancers, and reduced survival. Our study provided the first in vivo evidence that epigenetic alteration alone can cause cancer. It also has profound implications for future studies, since epigenetic changes are potentially reversible. Our findings provide hope for new epigenetic therapies and validate a novel approach for testing them.

Technical Abstract: Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated genomic targeting of DNA methylation. We used this system to target DNA methylation within the p16Ink4a promoter in mice in vivo. Engineered p16Ink4a promoter hypermethylation led to transcriptional suppression in somatic tissues during aging and increased the incidence of spontaneous cancers in these mice. Further, mice carrying a germline p16Ink4a mutation in one allele and a somatic epimutation in the other had accelerated tumor onset and substantially shortened tumor-free survival. Taken together, these results provide direct functional evidence that p16Ink4a epimutation drives tumor formation and malignant progression and validate a targeted methylation approach to epigenetic engineering.