title: Targeted p16(Ink4a) epimutation causes tumorigenesis and reduces survival in mice.
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 p16(Ink4a) promoter in mice in vivo. Engineered p16(Ink4a) 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 p16(Ink4a) 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 p16(Ink4a) epimutation drives tumor formation and malignant progression and validate a targeted methylation approach to epigenetic engineering.
authors: Da-Hai
authors: DH
authors: Yu
authors: Robert A
authors: RA
authors: Waterland
authors: Pumin
authors: P
authors: Zhang
authors: Deborah
authors: D
authors: Schady
authors: Miao-Hsueh
authors: MH
authors: Chen
authors: Yongtao
authors: Y
authors: Guan
authors: Manasi
authors: M
authors: Gadkari
authors: Lanlan
authors: L
authors: Shen
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004247:DNA; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004247:DNA