| Literature DB >> 30753828 |
Yong Tao1, Byunghak Kang1, Daniel A Petkovich1, Yuba R Bhandari1, Julie In2, Genevieve Stein-O'Brien3, Xiangqian Kong1, Wenbing Xie1, Nicholas Zachos2, Shinji Maegawa4, Himani Vaidya5, Stephen Brown1, Ray-Whay Chiu Yen1, Xiaojian Shao6, Jai Thakor1, Zhihao Lu7, Yi Cai1, Yuezheng Zhang8, Izaskun Mallona9, Miguel Angel Peinado9, Cynthia A Zahnow1, Nita Ahuja1, Elana Fertig3, Jean-Pierre Issa5, Stephen B Baylin10, Hariharan Easwaran11.
Abstract
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 BrafV600E, producing the typical human proximal BRAFV600E-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 BrafV600E-induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis.Entities:
Keywords: BRAF(V600E); CIMP; CpG-island DNA methylation; aging; cancer risk; colon adenocarcinomas; epigenetic silencing; transformation; tumor predisposition; tumorigenesis
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Year: 2019 PMID： 30753828 PMCID： PMC6636642 DOI： 10.1016/j.ccell.2019.01.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743