期刊
CANCER CELL
卷 35, 期 2, 页码 315-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.01.005
关键词
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资金
- National Institute Health, United States [R01CA185357, P50CA062924, P3ODK089502, R01CA170550]
- National Institute of Environmental Health Sciences, United States [R01ES011858]
- Hodson Trust
- MDxHealth
- Spanish Ministry of Science [SAF2015-64521-R]
We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by Braf(V600E), producing the typical human proximal BRAF(V600E)- driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitizes to Braf(V600E)-induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis.
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