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Title: Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600E-Induced Tumorigenesis.

Authors: Tao, Yong; Kang, Byunghak; Petkovich, Daniel A; Bhandari, Yuba R; In, Julie; Stein-O'Brien, Genevieve; Kong, Xiangqian; Xie, Wenbing; Zachos, Nicholas; Maegawa, Shinji; Vaidya, Himani; Brown, Stephen; Chiu Yen, Ray-Whay; Shao, Xiaojian; Thakor, Jai; Lu, Zhihao; Cai, Yi; Zhang, Yuezheng; Mallona, Izaskun; Peinado, Miguel Angel; Zahnow, Cynthia A; Ahuja, Nita; Fertig, Elana; Issa, Jean-Pierre; Baylin, Stephen B; Easwaran, Hariharan

Published In Cancer Cell, (2019 Feb 11)

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.

PubMed ID: 30753828 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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